+

US6191125B1 - Small molecule pipecolic acid derivative hair growth compositions and uses - Google Patents

Small molecule pipecolic acid derivative hair growth compositions and uses Download PDF

Info

Publication number
US6191125B1
US6191125B1 US09/089,373 US8937398A US6191125B1 US 6191125 B1 US6191125 B1 US 6191125B1 US 8937398 A US8937398 A US 8937398A US 6191125 B1 US6191125 B1 US 6191125B1
Authority
US
United States
Prior art keywords
straight
branched chain
alkyl
alkenyl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US09/089,373
Inventor
Joseph P. Steiner
Gregory S. Hamilton
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gliamed Inc
Original Assignee
GPI Nil Holdings Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GPI Nil Holdings Inc filed Critical GPI Nil Holdings Inc
Priority to US09/089,373 priority Critical patent/US6191125B1/en
Assigned to GUILFORD PHARMACEUTICALS INC. reassignment GUILFORD PHARMACEUTICALS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HAMILTON, GREGORY S., STEINER, JOSEPH P.
Assigned to GPI NIL HOLDINGS, INC. reassignment GPI NIL HOLDINGS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GUILFORD PHARMACEUTICALS INC.
Priority to US09/784,174 priority patent/US20010036952A1/en
Application granted granted Critical
Publication of US6191125B1 publication Critical patent/US6191125B1/en
Assigned to GLIAMED, INC. reassignment GLIAMED, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GPI IP, LLC, D/B/A MGL PHARMA
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/70—Biological properties of the composition as a whole

Definitions

  • This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using low molecular weight, small molecule pipecolic acid derivatives.
  • Hair loss occurs in a variety of situations. These situations include male pattern alopecia, alopecia senilis, alopecia areata, diseases accompanied by basic skin lesions or tumors, and systematic disorders such as nutritional disorders and internal secretion disorders.
  • the mechanisms causing hair loss are very complicated, but in some instances can be attributed to aging, genetic disposition, the activation of male hormones, the loss of blood supply to hair follicles, and scalp abnormalities.
  • the immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest. Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al., J. Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth in a dose-dependent manner.
  • alopecia areata One form of hair loss, alopecia areata, is known to be associated with autoimmune activities; hence, topically administered immunomodulatory compounds are expected to demonstrate efficacy for treating that type of hair loss.
  • the hair growth stimulating effects of FK506 have been the subject of an international patent filing covering FK506 and structures related thereto for hair growth stimulation (Honbo et al., EP 0 423 714 A2).
  • Honbo et al. discloses the use of relatively large tricyclic compounds, known for their immunosuppressive effects, as hair revitalizing agents.
  • immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects. Accordingly, there is a need for non-immunosuppressant, small molecule compounds which are useful as hair revitalizing compounds.
  • the present invention relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a low molecular weight, small molecule pipecolic acid derivative.
  • the present invention further relates to a pharmaceutical composition which comprises:
  • the pipecolic acid derivatives used in the inventive methods and pharmaceutical compositions include immunosuppressive and non-immunosuppressive compounds having an affinity for FKBP-type immunophilins, particularly FKBP12.
  • Non-immunosuppressive compounds as their name suggests, do not exert any significant immunosuppressive activity.
  • FIG. 1 is a photograph of mice treated with a vehicle after six weeks.
  • FIG. 1 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered.
  • FIG. 2 is a photograph of mice treated with 10 ⁇ M of GPI 1044 after six weeks.
  • FIG. 2 shows that 90% of the shaved area is covered with new hair growth when GPI 1044 is administered.
  • FIG. 3 is a bar graph plotting the hair growth scores of unshaven animals and shaven animals treated with a vehicle, GPI 1044 (1 ⁇ M, 3 ⁇ M and 10 ⁇ M), and related pipecolic acid derivative neuroimmunophilin FKBP ligands GPI 1116 (1 ⁇ M and 10 ⁇ M) and GPI 1102 (1 ⁇ M and 3 ⁇ M).
  • FIG. 4 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice treated with a vehicle, FK506, and related neuroimmunophilin FKBP ligands 14 days after treatment with each identified compound.
  • FIG. 4 demonstrates the remarkable early hair growth promoted by neuroimmunophilin FKBP ligands.
  • Alopecia refers to deficient hair growth and partial or complete loss of hair, including without limitation androgenic alopecia (male pattern baldness), toxic alopecia, alopecia senilis, alopecia areata, alopecia pelada and trichotillomania.
  • Alopecia results when the pilar cycle is disturbed. The most frequent phenomenon is a shortening of the hair growth or anagen phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs fall out.
  • Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental stresses, hormonal problems, and secondary effects of drugs.
  • GPI 1102 refers to 4-phenyl-1-(3-phenylpropyl) butyl 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate.
  • GPI 1116 refers to 1-phenethyl-3-phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate.
  • “Isomers” refer to different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. “Diastereoisomers” are stereoisomers which are not mirror images of each other. “Racemic mixture” means a mixture containing equal parts of individual enantiomers. “Non-racemic mixture” is a mixture containing unequal parts of individual enantiomers or stereoisomers.
  • “Pharmaceutically acceptable salt, ester, or solvate” refers to a salt, ester, or solvate of a subject compound which possesses the desired is pharmacological activity and which is neither biologically nor otherwise undesirable.
  • a salt, ester, or solvate can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanes
  • base salts, esters, or solvates include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts; N-methyl-D-glucamine; and salts with amino acids, such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates
  • Palm cycle refers to the life cycle of hair follicles, and includes three phases:
  • telogen phase hair is uniform in diameter with a slightly bulbous, non-pigmented root.
  • anagen phase hair has a large colored bulb at its root.
  • “Promoting hair growth” refers to maintaining, inducing, stimulating, accelerating, or revitalizing the germination of hair.
  • Treating alopecia refers to:
  • Terminal hair is coarse, pigmented, long hair in which the bulb of the hair follicle is seated deep in the dermis.
  • Vellus hair is fine, thin, non-pigmented short hair in which the hair bulb is located superficially in the dermis. As alopecia progresses, the hairs change from the terminal to the vellus type.
  • the present invention relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a pipecolic acid derivative.
  • the inventive method is particularly useful for treating male pattern alopecia, alopecia senilis, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapy such as chemotherapy and radiation, and alopecia resulting from systematic disorders such as nutritional disorders and internal secretion disorders.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the pipecolic acid derivatives used in the methods and pharmaceutical compositions of the present invention are low molecular weight, small molecule compounds having an affinity for FKBP-type immunophilins, such as FKBP12.
  • FKBP-type immunophilins such as FKBP12.
  • FKBP12 FKBP12
  • rotamase inhibiting compounds may be immunosuppressive or non-immunosuppressive. Examples of useful compounds are set forth below.
  • An exemplary pipecolic acid derivative is a compound of formula I
  • n 0-3;
  • A is CH 2 , O, NH, or N—(C 1 -C 4 alkyl);
  • B and D are independently Ar, C 5 -C 7 cycloalkyl substituted C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl, C 5 -C 7 cycloalkenyl substituted C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl, or Ar substituted C 1 -C 6 straight or branched chain alkyl or C 2 -C 6 straight or branched chain alkenyl, wherein in each case, one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, So, and SO 2 in chemically reasonable substitution patterns, or
  • Q is hydrogen, C 1 -C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl
  • T is Ar or C 5 -C 7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O—(C 1 -C 4 alkyl), O—(C 2 -C 4 alkenyl), and carbonyl;
  • Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF 3 , trifluoromethoxy, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, O—(C 1 -C 4 straight or branched chain alkyl), O—(C 2 -C 4 straight or branched chain alkenyl), O-benzyl, O-pheny
  • L is either hydrogen or U;
  • M is either oxygen or CH—U, provided that if L is hydrogen, then M is CH—U, or if M is oxygen then L is U;
  • U is hydrogen, O—(C 1 -C 4 straight or branched chain alkyl), O—(C 2 -C 4 straight or branched chain alkenyl), C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight is or branched chain alkenyl, C 5 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl substituted with C 1 -C 4 straight or branched chain alkyl or C 2 -C 4 straight or branched chain alkenyl, (C 1 -C 4 alkyl or C 2 -C 4 alkenyl)-Ar, or Ar;
  • J is hydrogen, C 1 or C 2 alkyl, or benzyl
  • K is C 1 -C 4 straight or branched chain alkyl, benzyl or cyclohexylmethyl
  • J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or SO 2 ;
  • said pipecolic acid derivative has an affinity for FKBP-type immunophilins.
  • A is O, NH, or N—(C 1 -C 4 alkyl);
  • B is hydrogen, CHL—Ar, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 5 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, Ar substituted C 1 -C 6 alkyl or C 2 -C 6 alkenyl, or
  • L and Q are independently hydrogen, C 1 -C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl;
  • T is Ar or C 5 -C 7 cyclohexyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O—(C 1 -C 4 alkyl), O—(C 2 -C 4 alkenyl), and carbonyl;
  • Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, CF 3 , C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, O—(C 1 -C 4 straight or branched chain alkyl), O—(C 2 -C 4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, and phenyl.
  • D is hydrogen or U;
  • E is oxygen or CH—U, provided that if D is hydrogen, then E is CH—U, or if E is oxygen, then D is U;
  • U is hydrogen, O—(C 1 -C 4 straight or branched chain alkyl), O—(C 2 -C 4 straight or branched chain alkenyl), C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 5 -C 7 -cycloalkyl, C 5 -C 7 cycloalkenyl substituted with C 1 -C 4 straight or branched chain alkyl or C 2 -C 4 straight or branched chain alkenyl, 2-indolyl, 3-indolyl, (C 1 -C 4 alkyl or C 2 -C 4 alkenyl)-Ar, or Ar;
  • J is hydrogen, C 1 or C 2 alkyl, or benzyl; K is C 1 -C 4 straight or branched chain alkyl, benzyl or cyclohexylethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or SO 2 .
  • a preferred pipecolic acid derivative is a compound of Formula III
  • n 2;
  • D is phenyl, methoxy, 2-furyl, or 3,4,5-trimethoxyphenyl
  • B is benzyl, 3-phenylpropyl, 4-(4-methoxyphenyl)butyl, 4-phenylbutyl, phenethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 3-phenoxybenzyl, 3-(3-indolyl)propyl, or 4-(4-methoxyphenyl)butyl;
  • D is phenyl
  • B is benzyl, 3-phenylpropyl, 4-(4-methoxyphenyl)butyl, 4-phenylbutyl, phenethyl, or 4-cyclohexylbutyl;
  • B is benzyl, 4-cyclohexylbutyl, 3-cyclohexylpropyl, or 3-cyclopentylpropyl;
  • D is 3,4,5-trimethoxyphenyl
  • B is 4-cyclohexylbutyl, 3-phenoxybenzyl, 4-phenylbutyl, 3- (3-indolyl) propyl, or 4- (4-methoxyphenyl) butyl.
  • the pipecolic acid derivative may also be a compound of formula IV
  • V is C, N, or S
  • J and K taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) selected from the group consisting of O, S, SO, SO 2 , N, NH, and NR;
  • R is either C 1 -C 9 straight or branched chain alkyl, C 2 -C 9 straight or branched chain alkenyl, C 3 -C 9 cycloakyl, C 5 -C 7 cycloalkenyl, or Ar 1 , wherein R is either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C 1 -C 6 straight or branched chain alkyl, C 2 -C 6 straight or branched chain alkenyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar 2 ;
  • Ar 1 and Ar 2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S;
  • A, B, D, L, M, and m are as defined in Formula I above;
  • said pipecolic acid derivative has an affinity for FKBP-type immunophilins.
  • All the compounds of Formulas I-IV possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual R- and S-stereoisomers.
  • the individual stereoisomers may be obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compounds of Formulas I-IV. It is understood that the compounds of Formulas I-IV encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers.
  • S-stereoisomers are used in the pharmaceutical compositions and methods of the present invention.
  • the compounds used in the inventive methods and pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12.
  • the inhibition of the prolyl peptidyl cis-trans isomerase activity of FKBP may be measured as an indicator of this affinity.
  • the cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para-nitroanilide from the trans form of the substrate.
  • a plastic cuvette In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/ml in 1 mM HCl) and 10 mL of test compound at various concentrations in dimethyl sulfoxide.
  • the reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL in 2.35 mM LiCl in trifluoroethanol).
  • the absorbance at 390 nm versus time is monitored for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance versus time data files.
  • the compounds used in the inventive methods and pharmaceutical compositions must readily affect the targeted areas.
  • the compounds are preferably administered topically to the skin.
  • the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Dosage levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg.
  • the specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration.
  • in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art.
  • the compounds can be administered with other hair revitalizing agents. Specific dose levels for the other hair revitalizing agents will depend upon the factors previously stated and the effectiveness of the drug combination.
  • C57 black 6 mice were used to demonstrate the hair revitalizing properties of pipecolic acid derivative GPI 1044 (compound 4), as well as related pipecolic acid derivative neuroimmunophilin FKBP ligands GPI 1102 and GPI 1116.
  • C57 black 6 mice approximately 7 weeks old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlaying dermal layers.
  • the animals were in anagen growth phase, as indicated by the pinkish color of the skin. Referring now to FIGS. 1 and 2, four animals were treated by topical administration with 20% propylene glycol vehicle (FIG.
  • FIG. 1 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth.
  • FIG. 2 shows that animals treated with 10 ⁇ M GPI 1044 exhibited dramatic hair growth, covering as much as 50% of the shaved area in some animals.
  • FIG. 3 compares the hair growth score of unshaven animals with the hair growth scores of shaven animals treated with a vehicle and GPI 1044 (1 ⁇ M, 3 ⁇ M and 10 ⁇ M), as well as related neuroimmunophilin FKBP ligands GPI 1116 (1 ⁇ M and 10 ⁇ M) and GPI 1102 (1 ⁇ M and 3 ⁇ M).
  • Experiment B C57 Black 6 mice were used to demonstrate the hair revitalizing properties of neuroimmunophilin FKBP ligands.
  • the animals were in a anagen growth phase when shaved.
  • Five animals per group were treated by topical administration with a vehicle, FK506, or a neuroimmunophilin FKBP ligand (GPI 1116 or 1206) at a concentration of one micromole per milliliter to the shaved area.
  • the animals were treated three times per week, and hair growth was evaluated 14 days after initiation of treatment. Hair growth was quantitated by the percent of shaved area covered by new hair growth, as scored by a blinded observer, on a scale of 0 (no growth) to five (complete hair regrowth in shaved area).
  • FIG. 4 shows that after 14 days, the animals treated with vehicle exhibited the beginning of growth in small tufts. In contrast, animals treated with one of the low molecular weight, small molecule, neuroimmunophilin FKBP ligands exhibited dramatic hair growth.
  • a lotion comprising the following composition may be prepared.
  • Ethanol 80.0 a pipecolic acid derivative as defined above 10.0 ⁇ -Tocopherol acetate 0.01
  • 5 ml of the lotion may be applied once or twice per day to a site having marked baldness or alopecia.
  • a lotion comprising the following composition shown may be prepared.
  • Ethanol 80.0 a pipecolic acid derivative as defined above 0.005 Hinokitol 0.01 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oil Purified water 19.0 Perfume and dye q.s.
  • the lotion may be applied by spraying once to 4 times per day to a site having marked baldness or alopecia.
  • An emulsion may be prepared from A phase and B phase having the following compositions.
  • the A phase and the B phase are respectively heated and melted and maintained at 80° c. Both phases are then mixed and cooled under stirring to normal temperature to obtain an emulsion.
  • the emulsion may be applied by spraying once to four times per day to a site having marked baldness or alopecia.
  • a cream may be prepared from A phase and B phase having the following compositions.
  • the A phase is heated and melted, and maintained at 70° C.
  • the B phase is added into the A phase and the mixture is stirred to obtain an emulsion.
  • the emulsion is then cooled to obtain a cream.
  • the cream may be applied once to 4 times per day to a site having marked baldness or alopecia.
  • a liquid comprising the following composition may be prepared.
  • the liquid may be applied once to 4 times per day to a site having marked baldness or alopecia.
  • a shampoo comprising the following composition may be prepared.
  • the shampoo may be used on the scalp once or twice per day.
  • a patient is suffering from alopecia senilis.
  • a pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from male pattern alopecia.
  • a pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from alopecia areata.
  • a pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from hair loss caused by skin lesions.
  • a pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from hair loss caused by tumors.
  • a pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from hair loss caused by a systematic disorder, such as a nutritional disorder or an internal secretion disorder.
  • a pipecolic acid derivative, or a pharmaceutical composition comprising the same may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from hair loss caused by chemotherapy.
  • a pipecolic acid derivative, or a pharmaceutical composition comprising the same may be administered to the patient. Increased hair growth is expected to occur following treatment.
  • a patient is suffering from hair loss caused by radiation.
  • a pipecolic acid derivative, or a pharmaceutical composition comprising the same may be administered to the patient. Increased hair growth is expected to occur following treatment.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Birds (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pyrrole Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using pipecolic acid derivatives.

Description

This application is a continuation-in-part of U.S. patent application Ser. No. 08/869,426, filed on Jun. 4, 1997, now U.S. Pat. No. 5,945,441, the entire contents of which are herein incorporated by reference.
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using low molecular weight, small molecule pipecolic acid derivatives.
2. Description of Related Art
Hair loss occurs in a variety of situations. These situations include male pattern alopecia, alopecia senilis, alopecia areata, diseases accompanied by basic skin lesions or tumors, and systematic disorders such as nutritional disorders and internal secretion disorders. The mechanisms causing hair loss are very complicated, but in some instances can be attributed to aging, genetic disposition, the activation of male hormones, the loss of blood supply to hair follicles, and scalp abnormalities.
The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest. Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al., J. Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth in a dose-dependent manner. One form of hair loss, alopecia areata, is known to be associated with autoimmune activities; hence, topically administered immunomodulatory compounds are expected to demonstrate efficacy for treating that type of hair loss. The hair growth stimulating effects of FK506 have been the subject of an international patent filing covering FK506 and structures related thereto for hair growth stimulation (Honbo et al., EP 0 423 714 A2). Honbo et al. discloses the use of relatively large tricyclic compounds, known for their immunosuppressive effects, as hair revitalizing agents.
The hair growth and revitalization effects of FK506 and related agents are disclosed in many U.S. patents (Goulet et al., U.S. Pat. No. 5,258,389; Luly et al., U.S. Pat. No. 5,457,111; Goulet et al., U.S. Pat. No. 5,532,248; Goulet et al., U.S. Pat. No. 5,189,042; and Ok et al., U.S. Pat. No. 5,208,241; Rupprecht et al., U.S. Pat. No. 5,284,840; Organ et al., U.S. Pat. No. 5,284,877). These patents claim FK506 related compounds. Although they do not claim methods of hair revitalization, they disclose the known use of FK506 for effecting hair growth. Similar to FK506 (and the claimed variations in the Honbo et al. patent), the compounds claimed in these patents are relatively large. Further, the cited patents relate to immunomodulatory compounds for use in autoimmune related diseases, for which FK506's efficacy is well known.
Other U.S. patents disclose the use of cyclosporin and related compounds for hair revitalization (Hauer et al., U.S. Pat. No. 5,342,625; Eberle, U.S. Pat. No. 5,284,826; Hewitt et al., U.S. Pat. No. 4,996,193). These patents also relate to compounds useful for treating autoimmune diseases and cite the known use of cyclosporin and related immunosuppressive compounds for hair growth.
However, immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects. Accordingly, there is a need for non-immunosuppressant, small molecule compounds which are useful as hair revitalizing compounds.
Hamilton and Steiner disclose in U.S. Pat. No. 5,614,547 novel pyrrolidine carboxylate compounds which bind to the immunophilin FKBP12 and stimulate nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that these non-immunosuppressant compounds promote hair growth with an efficacy similar to FK506. Yet their novel small molecule structure and non-immunosuppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art.
SUMMARY OF THE INVENTION
The present invention relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a low molecular weight, small molecule pipecolic acid derivative.
The present invention further relates to a pharmaceutical composition which comprises:
(i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal; and
(ii) a pharmaceutically acceptable carrier.
The pipecolic acid derivatives used in the inventive methods and pharmaceutical compositions include immunosuppressive and non-immunosuppressive compounds having an affinity for FKBP-type immunophilins, particularly FKBP12. Non-immunosuppressive compounds, as their name suggests, do not exert any significant immunosuppressive activity.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a photograph of mice treated with a vehicle after six weeks. FIG. 1 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered.
FIG. 2 is a photograph of mice treated with 10 μM of GPI 1044 after six weeks. FIG. 2 shows that 90% of the shaved area is covered with new hair growth when GPI 1044 is administered.
FIG. 3 is a bar graph plotting the hair growth scores of unshaven animals and shaven animals treated with a vehicle, GPI 1044 (1 μM, 3 μM and 10 μM), and related pipecolic acid derivative neuroimmunophilin FKBP ligands GPI 1116 (1 μM and 10 μM) and GPI 1102 (1 μM and 3 μM).
FIG. 4 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice treated with a vehicle, FK506, and related neuroimmunophilin FKBP ligands 14 days after treatment with each identified compound. FIG. 4 demonstrates the remarkable early hair growth promoted by neuroimmunophilin FKBP ligands.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
“Alopecia” refers to deficient hair growth and partial or complete loss of hair, including without limitation androgenic alopecia (male pattern baldness), toxic alopecia, alopecia senilis, alopecia areata, alopecia pelada and trichotillomania. Alopecia results when the pilar cycle is disturbed. The most frequent phenomenon is a shortening of the hair growth or anagen phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs fall out. Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental stresses, hormonal problems, and secondary effects of drugs.
“GPI 1044” refers to Compound 4.
“GPI 1102” refers to 4-phenyl-1-(3-phenylpropyl) butyl 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate.
“GPI 1116” refers to 1-phenethyl-3-phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate.
“GPI 1206” refers to a compound of formula
Figure US06191125-20010220-C00001
“Isomers” refer to different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. “Diastereoisomers” are stereoisomers which are not mirror images of each other. “Racemic mixture” means a mixture containing equal parts of individual enantiomers. “Non-racemic mixture” is a mixture containing unequal parts of individual enantiomers or stereoisomers.
“Pharmaceutically acceptable salt, ester, or solvate” refers to a salt, ester, or solvate of a subject compound which possesses the desired is pharmacological activity and which is neither biologically nor otherwise undesirable. A salt, ester, or solvate can be formed with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of base salts, esters, or solvates include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts; N-methyl-D-glucamine; and salts with amino acids, such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quarternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained.
“Pilar cycle” refers to the life cycle of hair follicles, and includes three phases:
(1) the anagen phase, the period of active hair growth which, insofar as scalp hair is concerned, lasts about three to five years;
(2) the catagen phase, the period when growth stops and the follicle atrophies which, insofar as scalp hair is concerned, lasts about one to two weeks; and
(3) the telogen phase, the rest period when hair progressively separates and finally falls out which, insofar as scalp hair is concerned, lasts about three to four months.
Normally 80 to 90 percent of the follicles are in the anagen phase, less than 1 percent being in the catagen phase, and the rest being in the telogen phase. In the telogen phase, hair is uniform in diameter with a slightly bulbous, non-pigmented root. By contrast, in the anagen phase, hair has a large colored bulb at its root.
“Promoting hair growth” refers to maintaining, inducing, stimulating, accelerating, or revitalizing the germination of hair.
“Treating alopecia” refers to:
(i) preventing alopecia in an animal which may be predisposed to alopecia; and/or
(ii) inhibiting, retarding or reducing alopecia; and/or
(iii) promoting hair growth; and/or
(iv) prolonging the anagen phase of the hair cycle; and/or
(v) converting vellus hair to growth as terminal hair. Terminal hair is coarse, pigmented, long hair in which the bulb of the hair follicle is seated deep in the dermis. Vellus hair, on the other hand, is fine, thin, non-pigmented short hair in which the hair bulb is located superficially in the dermis. As alopecia progresses, the hairs change from the terminal to the vellus type.
METHODS OF THE PRESENT INVENTION
The present invention relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a pipecolic acid derivative.
The inventive method is particularly useful for treating male pattern alopecia, alopecia senilis, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapy such as chemotherapy and radiation, and alopecia resulting from systematic disorders such as nutritional disorders and internal secretion disorders.
Pharmaceutical Compositions of the Present Invention
The present invention also relates to a pharmaceutical composition comprising:
(i) an effective amount of a pipecolic acid derivative for treating alopecia or promoting hair growth in an animal; and
(ii) a pharmaceutically acceptable carrier.
PIPECOLIC ACID DERIVATIVES
The pipecolic acid derivatives used in the methods and pharmaceutical compositions of the present invention are low molecular weight, small molecule compounds having an affinity for FKBP-type immunophilins, such as FKBP12. When a pipecolic acid derivative binds to an FKBP-type immunophilin, it has been found to inhibit the prolyl-peptidyl cis-trans isomerase, or rotamase, activity of the binding protein. Unexpectedly, the compounds have also been found to stimulate hair growth. These rotamase inhibiting compounds may be immunosuppressive or non-immunosuppressive. Examples of useful compounds are set forth below.
FORMULA I
An exemplary pipecolic acid derivative is a compound of formula I
Figure US06191125-20010220-C00002
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
m is 0-3;
A is CH2, O, NH, or N—(C1-C4 alkyl);
B and D are independently Ar, C5-C7 cycloalkyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkenyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, or Ar substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, wherein in each case, one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, So, and SO2 in chemically reasonable substitution patterns, or
Figure US06191125-20010220-C00003
wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and
T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O—(C1-C4 alkyl), O—(C2-C4 alkenyl), and carbonyl;
Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl;
L is either hydrogen or U; M is either oxygen or CH—U, provided that if L is hydrogen, then M is CH—U, or if M is oxygen then L is U;
U is hydrogen, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight is or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl; K is C1-C4 straight or branched chain alkyl, benzyl or cyclohexylmethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or SO2; and
said pipecolic acid derivative has an affinity for FKBP-type immunophilins.
Representative species of Formula I are presented in Table I.
TABLE I
Figure US06191125-20010220-C00004
Compound n m B D L
1 2 0 3-Phenyl- 3-(3-Pyridyl)- Phenyl
propyl propyl
2 2 0 3-Phenyl- 3-(2-Pyridyl)- Phenyl
propyl propyl
3 2 0 3-Phenyl- 2-(4-Methoxy- Phenyl
propyl phenyl)ethyl
4 2 0 3-Phenyl- 3-Phenylpropyl Phenyl
propyl
5 2 0 3-Phenyl- 3- Phenylpropyl 3,4,5-
propyl Trimeth-
oxyphenyl
6 2 0 3-Phenyl- 2-(3-Pyridyl)- 3,4,5-
propyl propyl Trimeth-
oxyphenyl
7 2 0 3-Phenyl- 3-(2-Pyridyl)- 3,4,5-
propyl propyl Trimeth-
oxyphenyl
8 2 0 3-Phenyl- 3-(4-Methoxy- 3,4,5-
propyl phenyl)propyl Trimeth-
oxyphenyl
9 2 0 3-Phenyl- 3-(3-Pyridyl)- 3-Iso-
propyl propyl propoxy-
phenyl
FORMULA II
U.S. Pat. No. 5,330,993, incorporated herein by reference, discloses an exemplary pipecolic acid derivative of Formula II
Figure US06191125-20010220-C00005
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A is O, NH, or N—(C1-C4 alkyl);
B is hydrogen, CHL—Ar, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, Ar substituted C1-C6 alkyl or C2-C6 alkenyl, or
Figure US06191125-20010220-C00006
wherein L and Q are independently hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and
T is Ar or C5-C7 cyclohexyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O—(C1-C4 alkyl), O—(C2-C4 alkenyl), and carbonyl;
Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, CF3, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, and phenyl.
D is hydrogen or U; E is oxygen or CH—U, provided that if D is hydrogen, then E is CH—U, or if E is oxygen, then D is U;
U is hydrogen, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7-cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, 2-indolyl, 3-indolyl, (C1-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl; K is C1-C4 straight or branched chain alkyl, benzyl or cyclohexylethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or SO2.
FORMULA III
A preferred pipecolic acid derivative is a compound of Formula III
Figure US06191125-20010220-C00007
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 2;
D is phenyl, methoxy, 2-furyl, or 3,4,5-trimethoxyphenyl; and
B is benzyl, 3-phenylpropyl, 4-(4-methoxyphenyl)butyl, 4-phenylbutyl, phenethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 3-phenoxybenzyl, 3-(3-indolyl)propyl, or 4-(4-methoxyphenyl)butyl;
provided that:
when D is phenyl, then B is benzyl, 3-phenylpropyl, 4-(4-methoxyphenyl)butyl, 4-phenylbutyl, phenethyl, or 4-cyclohexylbutyl;
when D is methoxy, B is benzyl, 4-cyclohexylbutyl, 3-cyclohexylpropyl, or 3-cyclopentylpropyl;
when D is 2-furyl, then B is benzyl; and
when D is 3,4,5-trimethoxyphenyl, then B is 4-cyclohexylbutyl, 3-phenoxybenzyl, 4-phenylbutyl, 3- (3-indolyl) propyl, or 4- (4-methoxyphenyl) butyl.
Representative species of Formula III are presented in Table II.
TABLE II
III
Figure US06191125-20010220-C00008
Compound B D n
10 Benzyl Phenyl 2
11 3-Phenylpropyl Phenyl 2
12 4-(4-Methoxyphenyl)- Phenyl 2
butyl
13 4-Phenylbutyl Phenyl 2
14 Phenethyl Phenyl 2
15 4-Cyclohexylbutyl Phenyl 2
16 Benzyl Methoxy 2
17 4-Cyclohexylbutyl Methoxy 2
18 3-Cyclohexylpropyl Methoxy 2
19 3-Cyclopentylpropyl Methoxy 2
20 Benzyl 2-Furyl 2
21 4- Cyclohexylbutyl 3,4,5- 2
Trimethoxyphenyl
22 3- Phenoxybenzyl 3,4,5- 2
Trimethoxyphenyl
23 4- Phenylbutyl 3,4,5- 2
Trimethoxyphenyl
24 3-(3-Indolyl)propyl 3,4,5- 2
Trimethoxyphenyl
25 4-(4-Methoxyphenyl)- 3,4,5- 2
butyl Trimethoxyphenyl
FORMULA IV
The pipecolic acid derivative may also be a compound of formula IV
Figure US06191125-20010220-C00009
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is C, N, or S;
J and K, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) selected from the group consisting of O, S, SO, SO2, N, NH, and NR;
R is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloakyl, C5-C7 cycloalkenyl, or Ar1, wherein R is either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
Ar1 and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S;
A, B, D, L, M, and m are as defined in Formula I above; and
said pipecolic acid derivative has an affinity for FKBP-type immunophilins.
All the compounds of Formulas I-IV possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual R- and S-stereoisomers. The individual stereoisomers may be obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compounds of Formulas I-IV. It is understood that the compounds of Formulas I-IV encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers. Preferably, S-stereoisomers are used in the pharmaceutical compositions and methods of the present invention.
Affinity for FKBP12
The compounds used in the inventive methods and pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12. The inhibition of the prolyl peptidyl cis-trans isomerase activity of FKBP may be measured as an indicator of this affinity.
K. Test Procedure
Inhibition of the peptidyl-prolyl isomerase (rotamase) activity of the compounds used in the inventive methods and pharmaceutical compositions can be evaluated by known methods described in the literature (Harding et al., Nature, 1989, 341:758-760; Holt et al. J. Am. Chem. Soc., 115:9923-9938). These values are obtained as apparent Ki's and are presented for representative compounds in TABLE III.
The cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para-nitroanilide from the trans form of the substrate.
The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change in first-order rate constant as a function of inhibitor concentration to yield the apparent Ki values.
In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/ml in 1 mM HCl) and 10 mL of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL in 2.35 mM LiCl in trifluoroethanol).
The absorbance at 390 nm versus time is monitored for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance versus time data files.
TABLE III
In Vitro Test Results - Formulas I-III
Compound Ki (μM)
10 1.5
13 0.35
14 1.1
15 0.4
16 80
17 6
18 20
19 35
20 3
21 0.04
22 0.018
23 0.019
24 0.017
25 0.013
Route of Administration
To effectively treat alopecia or promote hair growth, the compounds used in the inventive methods and pharmaceutical compositions must readily affect the targeted areas. For these purposes, the compounds are preferably administered topically to the skin.
For topical application to the skin, the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
Other routes of administration known in the pharmaceutical art are also contemplated by this invention.
Dosage
Dosage levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg. The specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration. Typically, in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art.
The compounds can be administered with other hair revitalizing agents. Specific dose levels for the other hair revitalizing agents will depend upon the factors previously stated and the effectiveness of the drug combination.
EXAMPLES
The following examples are illustrative of the present invention and are not intended to be limitations thereon. Unless otherwise indicated, all percentages are based upon 100% by weight of the final composition.
Example 1
In Vivo Hair Generation Tests With C57 Black 6 Mice
Experiment A: C57 black 6 mice were used to demonstrate the hair revitalizing properties of pipecolic acid derivative GPI 1044 (compound 4), as well as related pipecolic acid derivative neuroimmunophilin FKBP ligands GPI 1102 and GPI 1116. C57 black 6 mice, approximately 7 weeks old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlaying dermal layers. The animals were in anagen growth phase, as indicated by the pinkish color of the skin. Referring now to FIGS. 1 and 2, four animals were treated by topical administration with 20% propylene glycol vehicle (FIG. 1), and seven animals were treated by topical administration with 10 μM GPI 1044 (FIG. 2). The animals were treated with vehicle or GPI 1044 every 48 hours (3 applications total over the course of 5 days) and the hair growth was allowed to proceed for 6 weeks. Hair growth was quantitated by the percent of shaved area covered by new hair growth during this time period.
FIG. 1 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth. In contrast, FIG. 2 shows that animals treated with 10 μM GPI 1044 exhibited dramatic hair growth, covering as much as 50% of the shaved area in some animals. FIG. 3 compares the hair growth score of unshaven animals with the hair growth scores of shaven animals treated with a vehicle and GPI 1044 (1 μM, 3 μM and 10 μM), as well as related neuroimmunophilin FKBP ligands GPI 1116 (1 μM and 10 μM) and GPI 1102 (1 μM and 3 μM).
Experiment B: C57 Black 6 mice were used to demonstrate the hair revitalizing properties of neuroimmunophilin FKBP ligands. C57 Black 6 mice, 55 to 75 days old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlying dermal layers. The animals were in a anagen growth phase when shaved. Five animals per group were treated by topical administration with a vehicle, FK506, or a neuroimmunophilin FKBP ligand (GPI 1116 or 1206) at a concentration of one micromole per milliliter to the shaved area. The animals were treated three times per week, and hair growth was evaluated 14 days after initiation of treatment. Hair growth was quantitated by the percent of shaved area covered by new hair growth, as scored by a blinded observer, on a scale of 0 (no growth) to five (complete hair regrowth in shaved area).
FIG. 4 shows that after 14 days, the animals treated with vehicle exhibited the beginning of growth in small tufts. In contrast, animals treated with one of the low molecular weight, small molecule, neuroimmunophilin FKBP ligands exhibited dramatic hair growth.
Example 2
A lotion comprising the following composition may be prepared.
(%)
95% Ethanol 80.0
a pipecolic acid derivative as defined above 10.0
α-Tocopherol acetate 0.01
Ethylene oxide (40 mole) adducts of hardened 0.5
castor oil
purified water 9.0
perfume and dye q.s.
Into 95% ethanol are added a pipecolic acid derivative, α-tocopherol acetate, ethylene oxide (40 mole) adducts of hardened castor oil, perfume and a dye. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain a transparent liquid lotion.
5 ml of the lotion may be applied once or twice per day to a site having marked baldness or alopecia.
Example 3
A lotion comprising the following composition shown may be prepared.
(%)
95% Ethanol 80.0
a pipecolic acid derivative as defined above 0.005
Hinokitol 0.01
Ethylene oxide (40 mole) adducts of hardened 0.5
castor oil
Purified water 19.0
Perfume and dye q.s.
Into 95% ethanol are added a pipecolic acid derivative, hinokitol, ethylene oxide (40 mole) adducts of hardened castor oil, perfume, and a dye. The resulting mixture is stirred, and purified water is added to the mixture to obtain a transparent liquid lotion.
The lotion may be applied by spraying once to 4 times per day to a site having marked baldness or alopecia.
Example 4
An emulsion may be prepared from A phase and B phase having the following compositions.
(A phase) (%)
Whale wax 0.5
Cetanol 2.0
Petrolatum 5.0
Squalane 10.0
Polyoxyethylene (10 mole) monostearate 2.0
Sorbitan monooleate 1.0
a pipecolic acid derivative as defined above 0.01
(B phase) (%)
Glycerine 10.0
Purified water 69.0
Perfume, dye, and preservative q.s.
The A phase and the B phase are respectively heated and melted and maintained at 80° c. Both phases are then mixed and cooled under stirring to normal temperature to obtain an emulsion.
The emulsion may be applied by spraying once to four times per day to a site having marked baldness or alopecia.
Example 5
A cream may be prepared from A phase and B phase having the following compositions.
(A Phase) (%)
Fluid paraffin 5.0
Cetostearyl alcohol 5.5
Petrolatum 5.5
Glycerine monostearate 33.0
Polyoxyethylene (20 mole) 2-octyldodecyl 3.0
ether
Propylparaben 0.3
(B Phase) (%)
a pipecolic acid derivative as defined above 0.8
Glycerine 7.0
Dipropylene glycol 20.0
Polyethylene glycol 4000 5.0
Sodium Hexametaphosphate 0.005
Purified water 44.895
The A phase is heated and melted, and maintained at 70° C. The B phase is added into the A phase and the mixture is stirred to obtain an emulsion. The emulsion is then cooled to obtain a cream.
The cream may be applied once to 4 times per day to a site having marked baldness or alopecia.
Example 6
A liquid comprising the following composition may be prepared.
(%)
Polyoxyethylene butyl ether 20.0
Ethanol 50.0
a pipecolic acid derivative as defined above 0.001
Propylene glycol 5.0
Polyoxyethylene hardened castor oil 0.4
derivative (ethylene oxide 80 mole adducts)
Perfume q.s.
Purified water q.s.
Into ethanol are added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, a pipecolic acid derivative, and perfume. The resulting mixture is stirred, and purified water is added to the mixture to obtain a liquid.
The liquid may be applied once to 4 times per day to a site having marked baldness or alopecia.
Example 7
A shampoo comprising the following composition may be prepared.
(%)
Sodium laurylsulfate 5.0
Triethanolamine laurylsulfate 5.0
Betaine lauryldimethylaminoacetate 6.0
Ethylene glycol distearate 2.0
Polyethylene glycol 5.0
a pipecolic acid derivative as defined above 5.0
Ethanol 2.0
Perfume 0.3
Purified water 69.7
Into 69.7 of purified water are added 5.0 g of sodium laurylsulfate, 5.0 g of triethanolamine laurylsulfate, 6.0 g of betaine lauryldimethyl-aminoacetate. Then a mixture obtained by adding 5.0 g of a pipecolic acid derivative, 5.0 g of polyethylene glycol, and 2.0 g of ethylene glycol distearate to 2.0 g of ethanol, followed by stirring, and 0.3 g of perfume are successively added. The resulting mixture is heated and subsequently cooled to obtain a shampoo.
The shampoo may be used on the scalp once or twice per day.
Example 8
A patient is suffering from alopecia senilis. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example 9
A patient is suffering from male pattern alopecia. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example 10
A patient is suffering from alopecia areata. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example 11
A patient is suffering from hair loss caused by skin lesions. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example 12
A patient is suffering from hair loss caused by tumors. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example 13
A patient is suffering from hair loss caused by a systematic disorder, such as a nutritional disorder or an internal secretion disorder. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example 14
A patient is suffering from hair loss caused by chemotherapy. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
Example 15
A patient is suffering from hair loss caused by radiation. A pipecolic acid derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.
The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims (3)

We claim:
1. A method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of a compound of formula I
Figure US06191125-20010220-C00010
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A is O, NH, or N—(C1-C4 alkyl);
B and D are independently Ar, C5-C7 cycloalkyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkenyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, or Ar substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, wherein in each case, one or two carbon atom(s) of said alkyl or alkenyl is/are optionally substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, SO, and SO2, or
Figure US06191125-20010220-C00011
wherein Q is hydrogen, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl; and
T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O—(C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl;
Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which have in either or both rings a total of 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur; wherein Ar has 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl;
L is either hydrogen or U; M is either oxygen or CH—U, provided that if L is hydrogen, then M is CH—U, or if M is oxygen then L is U;
U is hydrogen, O—(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl; K is C1-C4 straight or branched chain alkyl, benzyl or cyclohexylmethyl; or J and K are taken together to form a 7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or SO2;
m is 0-3; and
said compound has an affinity for FKBP-type immunophilins.
2. A method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of a compound of formula II
Figure US06191125-20010220-C00012
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A is O, NH, or N—(C1-C4 alkyl);
B is hydrogen, CHL—Ar, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, Ar substituted C1-C6 alkyl or C2-C6 alkenyl, or
Figure US06191125-20010220-C00013
wherein L and Q are independently hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and
T is Ar or C5-C7 cyclohexyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O—(C1-C4 alkyl), O—(C2-C4 alkenyl), and carbonyl;
Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, CF3, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, and phenyl.
D is hydrogen or U; E is oxygen or CH—U, provided that if D is hydrogen, then E is CH—U, or if E is oxygen, then D is U;
U is hydrogen, O—(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7-cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, 2-indolyl, 3-indolyl, (C1-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl; K is C1-C4 straight or branched chain alkyl, benzyl or cyclohexylethyl; or J and K are taken together to form a 7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or SO2; and
said compound has an affinity for FKBP-type immunophilins.
3. A method for treating alopecia or promoting hair growth in an animal in need thereof, which comprises administering to said animal an effective amount of a compound of formula IV
Figure US06191125-20010220-C00014
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is C, N, or S;
J and K, taken together with V and the carbon atom to which they are respectively attached, form a 7 membered saturated or unsaturated heterocyclic ring having, in addition to V, one or more heteroatom(s) selected from the group consisting of O, S, SO, SO2, N, NH, and NR;
R is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloakyl, C5-C7 cycloalkenyl, or Ar1, wherein R is either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
Ar1 and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring has 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S;
A is O, NH, or N—(C1-C4 alkyl);
B and D are independently Ar, C5-C7 cycloalkyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkenyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, or Ar substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, wherein in each case, one or two carbon atom(s) of said alkyl or alkenyl is/are optionally substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, SO, and SO2, or
Figure US06191125-20010220-C00015
wherein O is hydrogen, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl; and
T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O—(C1-C4 alkyl), O—(C2-C4 alkenyl), and carbonyl;
Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which have in either or both rings a total of 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur; wherein Ar has 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O—(C1C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl;
L is either hydrogen or U; M is either oxygen or CH—U, provided that if L is hydrogen, then M is CH—U, or if M is oxygen then L is U;
U is hydrogen, O—(C1-C4 straight or branched chain alkyl), O—(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar;
m is 0-3; and
said compound has an affinity for FKBP-type immunophilins.
US09/089,373 1997-06-04 1998-06-03 Small molecule pipecolic acid derivative hair growth compositions and uses Expired - Fee Related US6191125B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/089,373 US6191125B1 (en) 1997-06-04 1998-06-03 Small molecule pipecolic acid derivative hair growth compositions and uses
US09/784,174 US20010036952A1 (en) 1997-06-04 2001-02-16 Small molecule pipecolic acid derivative hair growth compositions and uses

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/869,426 US5945441A (en) 1997-06-04 1997-06-04 Pyrrolidine carboxylate hair revitalizing agents
US09/089,373 US6191125B1 (en) 1997-06-04 1998-06-03 Small molecule pipecolic acid derivative hair growth compositions and uses

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08/869,426 Continuation-In-Part US5945441A (en) 1997-06-04 1997-06-04 Pyrrolidine carboxylate hair revitalizing agents

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/784,174 Division US20010036952A1 (en) 1997-06-04 2001-02-16 Small molecule pipecolic acid derivative hair growth compositions and uses

Publications (1)

Publication Number Publication Date
US6191125B1 true US6191125B1 (en) 2001-02-20

Family

ID=25353537

Family Applications (10)

Application Number Title Priority Date Filing Date
US08/869,426 Expired - Fee Related US5945441A (en) 1997-06-04 1997-06-04 Pyrrolidine carboxylate hair revitalizing agents
US09/089,832 Expired - Fee Related US6194440B1 (en) 1997-06-04 1998-06-03 Small molecule carbamate or urea hair growth compositions and uses
US09/089,415 Expired - Fee Related US6177455B1 (en) 1997-06-04 1998-06-03 Pyrrolidine derivative hair growth compositions and uses
US09/089,375 Expired - Fee Related US6004993A (en) 1997-06-04 1998-06-03 N-linked sulfonamide of heterocyclic thioester hair growth compounds and uses
US09/089,373 Expired - Fee Related US6191125B1 (en) 1997-06-04 1998-06-03 Small molecule pipecolic acid derivative hair growth compositions and uses
US09/359,709 Expired - Fee Related US6187806B1 (en) 1997-06-04 1999-07-23 N-linked sulfone of heterocyclic thioester hair growth compositions and uses
US09/369,860 Expired - Fee Related US6239164B1 (en) 1997-06-04 1999-08-09 Pyrrolidine carboxylate and pyrrolidine amide hair revitalizing agents
US09/784,174 Abandoned US20010036952A1 (en) 1997-06-04 2001-02-16 Small molecule pipecolic acid derivative hair growth compositions and uses
US09/791,661 Abandoned US20020037924A1 (en) 1997-06-04 2001-02-26 Small molecule carbamate or urea hair growth compositions and uses
US09/825,896 Abandoned US20010029263A1 (en) 1997-06-04 2001-04-05 Novel pyrrolidine carboxylate hair revitalizing agents

Family Applications Before (4)

Application Number Title Priority Date Filing Date
US08/869,426 Expired - Fee Related US5945441A (en) 1997-06-04 1997-06-04 Pyrrolidine carboxylate hair revitalizing agents
US09/089,832 Expired - Fee Related US6194440B1 (en) 1997-06-04 1998-06-03 Small molecule carbamate or urea hair growth compositions and uses
US09/089,415 Expired - Fee Related US6177455B1 (en) 1997-06-04 1998-06-03 Pyrrolidine derivative hair growth compositions and uses
US09/089,375 Expired - Fee Related US6004993A (en) 1997-06-04 1998-06-03 N-linked sulfonamide of heterocyclic thioester hair growth compounds and uses

Family Applications After (5)

Application Number Title Priority Date Filing Date
US09/359,709 Expired - Fee Related US6187806B1 (en) 1997-06-04 1999-07-23 N-linked sulfone of heterocyclic thioester hair growth compositions and uses
US09/369,860 Expired - Fee Related US6239164B1 (en) 1997-06-04 1999-08-09 Pyrrolidine carboxylate and pyrrolidine amide hair revitalizing agents
US09/784,174 Abandoned US20010036952A1 (en) 1997-06-04 2001-02-16 Small molecule pipecolic acid derivative hair growth compositions and uses
US09/791,661 Abandoned US20020037924A1 (en) 1997-06-04 2001-02-26 Small molecule carbamate or urea hair growth compositions and uses
US09/825,896 Abandoned US20010029263A1 (en) 1997-06-04 2001-04-05 Novel pyrrolidine carboxylate hair revitalizing agents

Country Status (12)

Country Link
US (10) US5945441A (en)
EP (3) EP0998263A1 (en)
JP (2) JP4068164B2 (en)
AT (1) ATE275930T1 (en)
AU (2) AU7716998A (en)
CA (2) CA2292965C (en)
DE (2) DE69836878D1 (en)
ES (1) ES2229498T3 (en)
MX (1) MXPA99010886A (en)
TW (3) TW490307B (en)
WO (2) WO1998055091A1 (en)
ZA (3) ZA984621B (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010029263A1 (en) * 1997-06-04 2001-10-11 Gpi Nil Holdings, Inc. Novel pyrrolidine carboxylate hair revitalizing agents
US20010041733A1 (en) * 1998-06-03 2001-11-15 Gpi Nil Holdings, Inc. Heterocyclic ester and amide hair growth compositions and uses
US6429215B1 (en) 1998-06-03 2002-08-06 Gpi Nil Holdings, Inc. N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
US20020198250A1 (en) * 1997-06-04 2002-12-26 Steiner Joseph P. Pyrrolidine derivative hair growth compositions and uses
US20050059693A1 (en) * 1997-06-04 2005-03-17 Gpi Nil Holdings, Inc. Heterocyclic thioester and ketone hair growth compositions and uses

Families Citing this family (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6218424B1 (en) * 1996-09-25 2001-04-17 Gpi Nil Holdings, Inc. Heterocyclic ketone and thioester compounds and uses
US5846979A (en) * 1997-02-28 1998-12-08 Gpi Nil Holdings, Inc. N-oxides of heterocyclic esters, amides, thioesters, and ketones
EP1084106A1 (en) 1998-06-03 2001-03-21 GPI NIL Holdings, Inc. N-linked sulfonamides of heterocyclic carboxylic acids or carboxylic acid isosteres
US6331537B1 (en) 1998-06-03 2001-12-18 Gpi Nil Holdings, Inc. Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds
SK18312000A3 (en) * 1998-06-03 2001-06-11 Gpi Nil Holdings, Inc. Aza-heterocyclic compounds used to treat neurological disorders and hair loss
AU1708299A (en) * 1998-06-03 1999-12-20 Amgen, Inc. Aza-heterocyclic compounds used to treat neurological disorders and hair loss
US6218423B1 (en) * 1998-08-14 2001-04-17 Gpi Nil Holdings, Inc. Pyrrolidine derivatives for vision and memory disorders
US7410995B1 (en) * 1998-08-14 2008-08-12 Gpi Nil Holdings Inc. N-linked sulfonamide of heterocyclic thioesters for vision and memory disorders
US7338976B1 (en) * 1998-08-14 2008-03-04 Gpi Nil Holdings, Inc. Heterocyclic esters or amides for vision and memory disorders
US6337340B1 (en) * 1998-08-14 2002-01-08 Gpi Nil Holdings, Inc. Carboxylic acids and isosteres of heterocyclic ring compounds having multiple heteroatoms for vision and memory disorders
US6384056B1 (en) * 1998-08-14 2002-05-07 Gpi Nil Holdings, Inc. Heterocyclic thioesters or ketones for vision and memory disorders
US6506788B1 (en) * 1998-08-14 2003-01-14 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioesters for vision and memory disorders
US6462072B1 (en) 1998-09-21 2002-10-08 Gpi Nil Holdings, Inc. Cyclic ester or amide derivatives
US6307049B1 (en) * 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
US6300341B1 (en) 1998-09-30 2001-10-09 The Procter & Gamble Co. 2-substituted heterocyclic sulfonamides
CN1367678A (en) * 1998-09-30 2002-09-04 宝洁公司 Method of treating hair loss using ketoamides
WO2001008685A1 (en) * 1999-07-30 2001-02-08 Vertex Pharmaceuticals Incorporated Acyclic and cyclic amine derivatives
WO2001010839A2 (en) * 1999-08-05 2001-02-15 The Procter & Gamble Company Multivalent substituted ketoamides and amides for treating hair loss
WO2001010836A1 (en) * 1999-08-05 2001-02-15 The Procter & Gamble Company Method of treating hair loss using multivalent ketoamides and amides
WO2001010837A1 (en) * 1999-08-05 2001-02-15 The Procter & Gamble Company Multivalent sulfonamides
AU6499000A (en) * 1999-08-05 2001-03-05 Procter & Gamble Company, The Multivalent compounds
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use
DE60026568D1 (en) 1999-12-21 2006-05-04 Mgi Gp Inc HYDANTOINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHOD FOR THEIR USE
US6593362B2 (en) * 2001-05-21 2003-07-15 Guilford Pharmaceuticals Inc. Non-peptidic cyclophilin binding compounds and their use
US7169564B1 (en) * 2001-06-26 2007-01-30 Anaderm Research Corporation FKBP51/52 and CyP40-mediated mammalian hair growth
US7598278B2 (en) * 2002-04-11 2009-10-06 L'oreal Administration of pyridinedicarboxylic acid compounds for stimulating or inducing the growth of human keratinous fibers and/or arresting their loss
AU2003257143A1 (en) * 2002-07-31 2004-02-16 Shaklee Corporation A method for maximizing scalp health and inducing enhanced visual and tactile hair quality
EP3431464A3 (en) 2003-08-06 2019-07-31 Senomyx Inc. Novel flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof
WO2005105022A1 (en) * 2004-04-28 2005-11-10 Yoshiyasu Ito Hair restorer
EP1838288A4 (en) * 2004-12-20 2010-08-04 Ariad Pharma Inc Therapeutic materials and methods
EP2100588A4 (en) * 2006-12-20 2011-01-19 Taisho Pharmaceutical Co Ltd PTOPHYLACTIC OR THERAPEUTIC AGENT AGAINST ALOPECIA
WO2008106091A1 (en) * 2007-02-26 2008-09-04 Yeda Research And Development Co. Ltd. Use of long-chain alcohol derivatives for the treatment of alopecia areata
TWI534142B (en) 2011-03-15 2016-05-21 大正製藥股份有限公司 Azole derivatives
JP6020396B2 (en) * 2012-09-12 2016-11-02 大正製薬株式会社 Medicaments containing azole derivatives
FR3030248B1 (en) 2014-12-22 2018-03-23 L'oreal PYRIDINE-DICARBOXYLIC ACID DERIVATIVE ASSOCIATION / PARTICULAR ANTIOXIDANT AGENT

Citations (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2505114A1 (en) 1975-02-07 1976-08-19 Koehler Valentin Scalp-care compsns contg. B gp. vitamins - and sulphanilamides, sulphonamides etc., reducing loss of hair, itching, dandruff and greying
EP0012401A1 (en) 1978-12-11 1980-06-25 Merck & Co. Inc. Carboxyalkyl dipeptide derivatives, process for preparing them and pharmaceutical composition containing them
US4310461A (en) 1980-06-23 1982-01-12 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
EP0048159A2 (en) 1980-09-17 1982-03-24 University Of Miami Novel carboxyalkyl peptides and thioethers and ethers of peptides as antihypertensive agents
EP0050800A1 (en) 1980-10-23 1982-05-05 Schering Corporation Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them
EP0073143A2 (en) 1981-08-21 1983-03-02 James Walter Ryan Novel complex amido and imido derivatives of carboxyalkyl peptides and thioethers and ethers of peptides
US4390695A (en) 1980-06-23 1983-06-28 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
EP0088350A1 (en) 1982-03-08 1983-09-14 Schering Corporation Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them
US4438031A (en) 1982-02-24 1984-03-20 American Home Products Corporation N-(Alkylsulfonyl)-L-proline amide and N-(alkylsulfonyl)-2-carboxylic acid amide-indoline derivatives
US4531964A (en) 1982-09-13 1985-07-30 Nippon Kayaku Kabushiki Kaisha Heterocyclic compound and a herbicidal composition containing said compound
US4574079A (en) 1983-05-27 1986-03-04 Gavras Haralambos P Radiolabeled angiotensin converting enzyme inhibitors for radiolabeling mammalian organ sites
US4578474A (en) 1980-06-23 1986-03-25 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
US4593102A (en) 1984-04-10 1986-06-03 A. H. Robins Company, Inc. N-[(amino)alkyl]-1-pyrrolidine, 1-piperidine and 1-homopiperidinecarboxamides (and thiocarboxamides) with sulfur linked substitution in the 2, 3 or 4-position
DE3508251A1 (en) 1985-03-08 1986-09-11 Merck Patent Gmbh, 6100 Darmstadt Dipeptides
EP0196841A1 (en) 1985-03-22 1986-10-08 Syntex (U.S.A.) Inc. N,N-dialkylguanidino dipeptides
WO1988000040A1 (en) 1986-07-02 1988-01-14 American Health Products Corporation Topical hair growing composition and kit
EP0260118A1 (en) 1986-09-10 1988-03-16 Syntex (U.S.A.) Inc. Selective amidination of diamines
WO1988009789A2 (en) 1987-06-03 1988-12-15 Polifarma S.P.A. 3-indolepyruvic acid derivatives and pharmaceutical use thereof
US4808573A (en) 1980-10-23 1989-02-28 Schering Corporation Carboxyalkyl dipeptides and anti-hypertensive use thereof
WO1989006234A1 (en) 1987-12-28 1989-07-13 Bazzano Gail S N,n-substituted amines and use thereof in hair growth promotion
EP0333174A2 (en) 1988-03-16 1989-09-20 Fujisawa Pharmaceutical Co., Ltd. Peptide compounds, processes for preparation thereof and pharmaceutical composition comprising the same
EP0352000A2 (en) 1988-07-08 1990-01-24 Smithkline Beecham Corporation Retroviral protease binding peptides
DE3931051A1 (en) 1988-09-22 1990-03-29 Hoechst Ag New herbicidal amine salts of herbicidal acids
EP0378318A1 (en) 1989-01-11 1990-07-18 Merck & Co. Inc. Process for synthesis of FK-506 and tricarbonyl intermediates
WO1990012805A1 (en) 1989-04-15 1990-11-01 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Postostatin and related compound thereof, or their salts
EP0405994A2 (en) 1989-06-30 1991-01-02 Merck & Co. Inc. Synthetic process for FK-506 type macrolide intermediates
US4996193A (en) 1989-03-03 1991-02-26 The Regents Of The University Of California Combined topical and systemic method of administration of cyclosporine
EP0419049A1 (en) 1989-08-22 1991-03-27 Merck Frosst Canada Inc. (Quinolin-2-ylmethoxy) indoles as inhibitors of the biosynthesis of leukotrienes
EP0420707A1 (en) 1989-08-29 1991-04-03 L'oreal Compositions to be used to reduce hair-loss and to induce and stimulate its growth, containing derivatives of 2-aminopyrimidine 3-oxide and new compounds derived from 2-aminopyrimidine 3-oxide
WO1991004985A1 (en) 1989-09-29 1991-04-18 Pharma Mar S.A. Dehydrodidemnin b
EP0423714A2 (en) 1989-10-16 1991-04-24 Fujisawa Pharmaceutical Co., Ltd. Hair revitalizing agent
EP0443983A1 (en) 1990-02-19 1991-08-28 Ciba-Geigy Ag Acyl compounds
WO1991013088A1 (en) 1990-02-28 1991-09-05 President And Fellows Of Harvard College Terminally blocked antiviral peptides
DE4015255A1 (en) 1990-05-12 1991-11-14 Hoechst Ag OXALYL-AMINOSA-E-LEED DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICAMENT FOR INHIBITING THE PROLYL HYDROXYLASE
WO1992000278A1 (en) 1990-07-02 1992-01-09 Vertex Pharmaceuticals Incorporated Novel immunosuppressive compounds
EP0468339A2 (en) 1990-07-27 1992-01-29 Nippon Kayaku Kabushiki Kaisha Alpha-keto-amide derivatives having protease inhibiting activity
EP0471135A2 (en) 1990-08-14 1992-02-19 Kenneth M. Hallam Compositions, medicaments and methods for the promotion of hair growth
GB2247456A (en) 1990-09-03 1992-03-04 Fujisawa Pharmaceutical Co Tetrahydropyrane compounds, a process for their production and a pharmaceutical composition containing the same
WO1992003472A1 (en) 1990-08-24 1992-03-05 The Upjohn Company Peptides containing amino-polyols as transition-state mimics
WO1992004370A1 (en) 1990-08-29 1992-03-19 Vertex Pharmaceuticals Incorporated Modified di- and tripeptidyl immunosuppressive compounds
JPH04149166A (en) 1990-10-12 1992-05-22 Nippon Kayaku Co Ltd Novel keto acid amide derivative
EP0494005A1 (en) 1990-12-28 1992-07-08 L'oreal Multicomponent agent or kit for the preparation of the sulphoconjugated forms of pyridino-, pyrimidino- or triazino-N-oxyde compounds and method of application thereof
US5147877A (en) 1991-04-18 1992-09-15 Merck & Co. Inc. Semi-synthetic immunosuppressive macrolides
WO1992016501A1 (en) 1991-03-20 1992-10-01 Vertex Pharmaceuticals Incorporated Tetrahydroxyalkane derivatives as inhibitors of hiv aspartyl protease
WO1992018478A1 (en) 1991-04-09 1992-10-29 Boehringer Mannheim Italia S.P.A. Heterocyclic amines useful in the therapy of asthma and inflammation of the respiratory tract
WO1992019593A1 (en) 1991-05-09 1992-11-12 Vertex Pharmaceuticals Incorporated Novel immunosuppressive compounds
WO1992019745A1 (en) 1991-05-08 1992-11-12 Vertex Pharmaceuticals Incorporated Rfkbp: a novel prolyl isomerase and rapamycin/fk506 binding protein
WO1992021313A2 (en) 1991-05-24 1992-12-10 Vertex Pharmaceuticals Incorporated Novel immunosuppressive compounds
EP0519819A1 (en) 1991-06-20 1992-12-23 L'oreal Composition for use to reduce hair loss and to induce and stimulate its growth, containing derivatives of 2,4,6-triaminopyrimidin-N-oxide and the new derivatives of 2,4,6-triaminopyrimidin-N-oxide
US5189042A (en) 1991-08-22 1993-02-23 Merck & Co. Inc. Fluoromacrolides having immunosuppressive activity
WO1993007269A1 (en) 1991-10-11 1993-04-15 Vertex Pharmaceuticals Incorporated ISOLATION OF AN Mr 52,000 FK506 BINDING PROTEIN AND MOLECULAR CLONING OF A CORRESPONDING HUMAN cDNA
US5208241A (en) 1991-09-09 1993-05-04 Merck & Co., Inc. N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity
WO1993013066A1 (en) 1991-12-20 1993-07-08 Syntex (U.S.A.) Inc. Cyclic amides of 3-amino-2-hydroxy-carboxylic acids as hiv-protease inhibitors
JPH05178824A (en) 1991-08-05 1993-07-20 Takeda Chem Ind Ltd Asparagine derivative and its use
WO1993014072A1 (en) 1992-01-07 1993-07-22 British Bio-Technology Limited Amino acid derivatives as paf-receptor antagonists
WO1993014762A1 (en) 1992-01-27 1993-08-05 Merck & Co., Inc. 17β-HYDROXYBENZOYL-4-AZA-5α-ANDROST-1-EN-3-ONES USEFUL TO TREAT BALDNESS
WO1993018736A1 (en) 1992-03-19 1993-09-30 Armand Pardo Cosmetic hair care compositions for treating hair loss
US5252579A (en) 1993-02-16 1993-10-12 American Home Products Corporation Macrocyclic immunomodulators
EP0564924A2 (en) 1992-04-08 1993-10-13 Bayer Corporation 2-Oxoethyl derivatives as immunosuppressants
US5258389A (en) 1992-11-09 1993-11-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives
WO1993023548A2 (en) 1992-05-20 1993-11-25 Vertex Pharmaceuticals Incorporated METHOD OF DETECTING TISSUE-SPECIFIC FK506 BINDING PROTEIN MESSENGER RNAs AND USES THEREOF
EP0572365A2 (en) 1992-05-29 1993-12-01 NUOVO CONSORZIO SANITARIO NAZIONALE del Dott. Paolo Malizia & C. - S.A.S. Heteroprostanoids, process for their production and therapeutical use thereof
WO1993025546A1 (en) 1992-06-17 1993-12-23 Merck Frosst Canada Inc. Bicyclic(azaaromatic)indoles as inhibitors of leukotriene biosynthesis
US5284877A (en) 1992-06-12 1994-02-08 Merck & Co., Inc. Alkyl and alkenyl macrolides having immunosuppressive activity
US5284840A (en) 1992-06-12 1994-02-08 Merck & Co., Inc. Alkylidene macrolides having immunosuppressive activity
US5284826A (en) 1989-07-24 1994-02-08 Sandoz Ltd. 0-hydroxyethyl and acyloxyethyl derivatives of [ser]8 cyclosporins
WO1994003476A1 (en) 1992-07-31 1994-02-17 Farmitalia Carlo Erba S.R.L. 17β-SUBSTITUTED 4-AZA-5α-ANDROSTAN-3-ONE DERIVATIVES
US5292747A (en) 1990-08-07 1994-03-08 Hoffman-La Roche Inc. Substituted pyrroles
US5294603A (en) 1980-09-12 1994-03-15 The Board Of Trustees Of The University Of Illinois Pharmaceutical compositions containing didemnins
WO1994005639A1 (en) 1992-09-08 1994-03-17 Vertex Pharmaceuticals Incorporated Sulfonamide inhibitors of hiv-aspartyl protease
WO1994007858A1 (en) 1992-09-28 1994-04-14 Vertex Pharmaceuticals Incorporated 1-(2-oxo-acetyl)-piperidine-2-carboxylic acid derivatives as multi-drug-resistent cancer cell sensitizers
US5319098A (en) 1993-05-18 1994-06-07 Celgene Corporation Process for the stereoselective preparation of L-alanyl-L-proline
WO1994013629A1 (en) 1992-12-11 1994-06-23 Vertex Pharmaceuticals Incorporated Mannitol derivatives and their use as inhibitors of aspartyl protease
US5342625A (en) 1988-09-16 1994-08-30 Sandoz Ltd. Pharmaceutical compositions comprising cyclosporins
US5359138A (en) 1989-04-15 1994-10-25 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Poststatin and related compounds or salts thereof
WO1995002684A1 (en) 1993-07-16 1995-01-26 The Board Of Trustees Of The Leland Stanford Junior University Regulated apoptosis
US5385918A (en) 1993-02-09 1995-01-31 Miles Inc. Aminomethylene-peptides as immunosuppressants
US5385908A (en) 1993-11-22 1995-01-31 American Home Products Corporation Hindered esters of rapamycin
US5414083A (en) 1993-01-22 1995-05-09 Chemie Linz Gesellschaft M.B.H. Method for the production of N-cyclic and N,N'-dicyclic ureas and their use as chemical solvents
EP0652229A2 (en) 1993-10-05 1995-05-10 ISAGRO S.p.A. Oligopeptides with fungicidal activity
WO1995012572A1 (en) 1993-11-04 1995-05-11 Abbott Laboratories Cyclobutane derivatives as inhibitors of squalene synthetase and protein farnesyltransferase
US5457111A (en) 1991-09-05 1995-10-10 Abbott Laboratories Macrocyclic immunomodulators
US5470878A (en) 1993-03-31 1995-11-28 Cell Therapeutics, Inc. Cell signaling inhibitors
US5472687A (en) 1985-07-18 1995-12-05 Proctor; Peter H. Topical pyridine N-oxides
US5506228A (en) 1995-02-23 1996-04-09 Merck & Co., Inc. 2,6-diaryl pyridazinones with immunosuppressant activity
US5532248A (en) 1991-05-13 1996-07-02 Merck Co., Inc. O-aryl,O-alkyl, and O-alkenyl-macrolides having immunosuppressive activity
US5543423A (en) 1994-11-16 1996-08-06 Vertex Pharmaceuticals, Incorporated Amino acid derivatives with improved multi-drug resistance activity
US5614547A (en) 1995-06-07 1997-03-25 Guilford Pharmaceuticals Inc. Small molecule inhibitors of rotamase enzyme
US5620971A (en) 1991-05-09 1997-04-15 Vertex Pharmaceuticals Incorporated Biologically active acylated amino acid derivatives
US5631017A (en) 1993-03-26 1997-05-20 Beth Israel Deaconess Medical Center, Inc. Topical application of buspirone for treatment of pathological conditions associated with immune responses
US5703088A (en) 1989-08-21 1997-12-30 Beth Israel Deaconess Medical Center, Inc. Topical application of spiperone or derivatives thereof for treatment of pathological conditions associated with immune responses
US5714510A (en) 1985-07-18 1998-02-03 Proctor; Peter H. Topical proxyl composition and method
EP0823419A2 (en) 1996-08-09 1998-02-11 Takeda Chemical Industries, Ltd. Dimethylpropanediol compounds

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4070361A (en) 1977-04-21 1978-01-24 E. R. Squibb & Sons, Inc. Mercaptoalkylsulfonyl proline and pipecolic acid and esters thereof
GB8630721D0 (en) * 1986-12-23 1987-02-04 Unilever Plc Cosmetic compositions
LU86959A1 (en) * 1987-07-31 1989-03-08 Oreal NOVEL DERIVATIVES OF UREYLENE TRIAMINO-2,4,6 PYRIMIDINE OXIDE-3, THEIR PREPARATION AND THEIR USE IN COSMETICS AND DERMOPHARMACY
GB2216003B (en) * 1988-02-18 1992-06-10 Toyama Chemical Co Ltd Hair restorer
ZA927782B (en) * 1991-10-11 1993-04-28 Ciba Geigy Novel herbicides.
US5723490A (en) 1992-09-08 1998-03-03 Vertex Pharmaceuticals Incorporated THF-containing sulfonamide inhibitors of aspartyl protease
US5482284A (en) 1993-08-09 1996-01-09 Vandever; Claude S. Golf address and stance teaching and practice device
EP0748221B1 (en) 1993-11-04 1999-04-14 Merck & Co. Inc. 7-substituted-4-aza-steroid derivatives as 5-alpha- reductase inhibitors
CA2183653A1 (en) 1994-03-07 1995-09-14 Roger Dennis Tung Sulphonamide derivatives as aspartyl protease inhibitors
US5744485A (en) 1994-03-25 1998-04-28 Vertex Pharmaceuticals Incorporated Carbamates and ureas as modifiers of multi-drug resistance
US5488816A (en) 1994-07-21 1996-02-06 Boehringer Mannheim Corporation Method and apparatus for manufacturing a coagulation assay device in a continuous manner
US5574011A (en) * 1995-04-04 1996-11-12 Tien; Henry C. Compositions and methods for the treatment of male-pattern baldness
US5691372A (en) 1995-04-19 1997-11-25 Vertex Pharmaceuticals Incorporated Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease
US5726184A (en) 1995-05-19 1998-03-10 Vertex Pharmaceuticals Incorporated Tetralin compounds with improved MDR activity
US6037370A (en) * 1995-06-08 2000-03-14 Vertex Pharmaceuticals Incorporated Methods and compositions for stimulating neurite growth
US5801197A (en) * 1995-10-31 1998-09-01 Gpi Nil Holdings, Inc. Rotamase enzyme activity inhibitors
CA2244363C (en) * 1996-02-28 2006-11-14 Ariad Gene Therapeutics, Inc. Synthetic derivatives of rapamycin as multimerizing agents for chimeric proteins with immunophilin-derived domains
US5717092A (en) * 1996-03-29 1998-02-10 Vertex Pharmaceuticals Inc. Compounds with improved multi-drug resistance activity
US5786378A (en) * 1996-09-25 1998-07-28 Gpi Nil Holdings, Inc. Heterocyclic thioesters
US5840736A (en) 1996-11-13 1998-11-24 Vertex Pharmaceuticals Incorporated Methods and compositions for stimulating neurite growth
US5811434A (en) 1996-11-13 1998-09-22 Vertex Pharmacueticals Incorporated Methods and compositions for stimulating neurite growth
US5780484A (en) 1996-11-13 1998-07-14 Vertex Pharmaceuticals Incorporated Methods for stimulating neurite growth with piperidine compounds
PT944645E (en) 1996-12-06 2005-06-30 Vertex Pharma INHIBITORS OF INTERLEUCINA CONVERTER ENZYME 1BETA
US6121273A (en) * 1996-12-31 2000-09-19 Gpi Nil Holdings, Inc N-linked sulfonamides of heterocyclic thioesters
US5874449A (en) * 1996-12-31 1999-02-23 Gpi Nil Holdings, Inc. N-linked sulfonamides of heterocyclic thioesters
US6187784B1 (en) * 1998-06-03 2001-02-13 Gpi Nil Holdings, Inc. Pipecolic acid derivative hair growth compositions and uses
US5945441A (en) * 1997-06-04 1999-08-31 Gpi Nil Holdings, Inc. Pyrrolidine carboxylate hair revitalizing agents
US6271244B1 (en) * 1998-06-03 2001-08-07 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses
US6187796B1 (en) * 1998-06-03 2001-02-13 Gpi Nil Holdings, Inc. Sulfone hair growth compositions and uses
US6172087B1 (en) * 1998-06-03 2001-01-09 Gpi Nil Holding, Inc. N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
US6218423B1 (en) * 1998-08-14 2001-04-17 Gpi Nil Holdings, Inc. Pyrrolidine derivatives for vision and memory disorders

Patent Citations (100)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2505114A1 (en) 1975-02-07 1976-08-19 Koehler Valentin Scalp-care compsns contg. B gp. vitamins - and sulphanilamides, sulphonamides etc., reducing loss of hair, itching, dandruff and greying
EP0012401A1 (en) 1978-12-11 1980-06-25 Merck & Co. Inc. Carboxyalkyl dipeptide derivatives, process for preparing them and pharmaceutical composition containing them
US4374829A (en) 1978-12-11 1983-02-22 Merck & Co., Inc. Aminoacid derivatives as antihypertensives
US4310461A (en) 1980-06-23 1982-01-12 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
US4390695A (en) 1980-06-23 1983-06-28 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
US4578474A (en) 1980-06-23 1986-03-25 E. R. Squibb & Sons, Inc. Imido, amido and amino derivatives of mercaptoacyl prolines and pipecolic acids
US5294603A (en) 1980-09-12 1994-03-15 The Board Of Trustees Of The University Of Illinois Pharmaceutical compositions containing didemnins
EP0048159A2 (en) 1980-09-17 1982-03-24 University Of Miami Novel carboxyalkyl peptides and thioethers and ethers of peptides as antihypertensive agents
US4818749A (en) 1980-10-23 1989-04-04 Schering Corporation Carboxyalkyl dipeptides and medical use thereof in treating hypertension and congestive heart failure
EP0050800A1 (en) 1980-10-23 1982-05-05 Schering Corporation Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them
US4808573A (en) 1980-10-23 1989-02-28 Schering Corporation Carboxyalkyl dipeptides and anti-hypertensive use thereof
EP0073143A2 (en) 1981-08-21 1983-03-02 James Walter Ryan Novel complex amido and imido derivatives of carboxyalkyl peptides and thioethers and ethers of peptides
US4438031A (en) 1982-02-24 1984-03-20 American Home Products Corporation N-(Alkylsulfonyl)-L-proline amide and N-(alkylsulfonyl)-2-carboxylic acid amide-indoline derivatives
EP0088350A1 (en) 1982-03-08 1983-09-14 Schering Corporation Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them
US4531964A (en) 1982-09-13 1985-07-30 Nippon Kayaku Kabushiki Kaisha Heterocyclic compound and a herbicidal composition containing said compound
US4574079A (en) 1983-05-27 1986-03-04 Gavras Haralambos P Radiolabeled angiotensin converting enzyme inhibitors for radiolabeling mammalian organ sites
US4593102A (en) 1984-04-10 1986-06-03 A. H. Robins Company, Inc. N-[(amino)alkyl]-1-pyrrolidine, 1-piperidine and 1-homopiperidinecarboxamides (and thiocarboxamides) with sulfur linked substitution in the 2, 3 or 4-position
DE3508251A1 (en) 1985-03-08 1986-09-11 Merck Patent Gmbh, 6100 Darmstadt Dipeptides
EP0196841A1 (en) 1985-03-22 1986-10-08 Syntex (U.S.A.) Inc. N,N-dialkylguanidino dipeptides
US5714510A (en) 1985-07-18 1998-02-03 Proctor; Peter H. Topical proxyl composition and method
US5472687A (en) 1985-07-18 1995-12-05 Proctor; Peter H. Topical pyridine N-oxides
WO1988000040A1 (en) 1986-07-02 1988-01-14 American Health Products Corporation Topical hair growing composition and kit
EP0260118A1 (en) 1986-09-10 1988-03-16 Syntex (U.S.A.) Inc. Selective amidination of diamines
WO1988009789A2 (en) 1987-06-03 1988-12-15 Polifarma S.P.A. 3-indolepyruvic acid derivatives and pharmaceutical use thereof
WO1989006234A1 (en) 1987-12-28 1989-07-13 Bazzano Gail S N,n-substituted amines and use thereof in hair growth promotion
EP0333174A2 (en) 1988-03-16 1989-09-20 Fujisawa Pharmaceutical Co., Ltd. Peptide compounds, processes for preparation thereof and pharmaceutical composition comprising the same
EP0352000A2 (en) 1988-07-08 1990-01-24 Smithkline Beecham Corporation Retroviral protease binding peptides
US5342625A (en) 1988-09-16 1994-08-30 Sandoz Ltd. Pharmaceutical compositions comprising cyclosporins
DE3931051A1 (en) 1988-09-22 1990-03-29 Hoechst Ag New herbicidal amine salts of herbicidal acids
EP0378318A1 (en) 1989-01-11 1990-07-18 Merck & Co. Inc. Process for synthesis of FK-506 and tricarbonyl intermediates
US4996193A (en) 1989-03-03 1991-02-26 The Regents Of The University Of California Combined topical and systemic method of administration of cyclosporine
WO1990012805A1 (en) 1989-04-15 1990-11-01 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Postostatin and related compound thereof, or their salts
US5359138A (en) 1989-04-15 1994-10-25 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Poststatin and related compounds or salts thereof
EP0405994A2 (en) 1989-06-30 1991-01-02 Merck & Co. Inc. Synthetic process for FK-506 type macrolide intermediates
US5284826A (en) 1989-07-24 1994-02-08 Sandoz Ltd. 0-hydroxyethyl and acyloxyethyl derivatives of [ser]8 cyclosporins
US5703088A (en) 1989-08-21 1997-12-30 Beth Israel Deaconess Medical Center, Inc. Topical application of spiperone or derivatives thereof for treatment of pathological conditions associated with immune responses
EP0419049A1 (en) 1989-08-22 1991-03-27 Merck Frosst Canada Inc. (Quinolin-2-ylmethoxy) indoles as inhibitors of the biosynthesis of leukotrienes
EP0420707A1 (en) 1989-08-29 1991-04-03 L'oreal Compositions to be used to reduce hair-loss and to induce and stimulate its growth, containing derivatives of 2-aminopyrimidine 3-oxide and new compounds derived from 2-aminopyrimidine 3-oxide
WO1991004985A1 (en) 1989-09-29 1991-04-18 Pharma Mar S.A. Dehydrodidemnin b
EP0423714A2 (en) 1989-10-16 1991-04-24 Fujisawa Pharmaceutical Co., Ltd. Hair revitalizing agent
EP0443983A1 (en) 1990-02-19 1991-08-28 Ciba-Geigy Ag Acyl compounds
US5447915A (en) 1990-02-28 1995-09-05 President And Fellows Of Harvard College Terminally blocked antiviral peptides
WO1991013088A1 (en) 1990-02-28 1991-09-05 President And Fellows Of Harvard College Terminally blocked antiviral peptides
DE4015255A1 (en) 1990-05-12 1991-11-14 Hoechst Ag OXALYL-AMINOSA-E-LEED DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICAMENT FOR INHIBITING THE PROLYL HYDROXYLASE
US5192773A (en) 1990-07-02 1993-03-09 Vertex Pharmaceuticals, Inc. Immunosuppressive compounds
US5516797A (en) 1990-07-02 1996-05-14 Vertex Pharmaceuticals, Incorporated Immunosuppressive compounds
US5330993A (en) 1990-07-02 1994-07-19 Vertex Pharmaceuticals, Inc. Immunosuppressive compounds
WO1992000278A1 (en) 1990-07-02 1992-01-09 Vertex Pharmaceuticals Incorporated Novel immunosuppressive compounds
EP0468339A2 (en) 1990-07-27 1992-01-29 Nippon Kayaku Kabushiki Kaisha Alpha-keto-amide derivatives having protease inhibiting activity
US5292747A (en) 1990-08-07 1994-03-08 Hoffman-La Roche Inc. Substituted pyrroles
EP0471135A2 (en) 1990-08-14 1992-02-19 Kenneth M. Hallam Compositions, medicaments and methods for the promotion of hair growth
WO1992003472A1 (en) 1990-08-24 1992-03-05 The Upjohn Company Peptides containing amino-polyols as transition-state mimics
WO1992004370A1 (en) 1990-08-29 1992-03-19 Vertex Pharmaceuticals Incorporated Modified di- and tripeptidyl immunosuppressive compounds
GB2247456A (en) 1990-09-03 1992-03-04 Fujisawa Pharmaceutical Co Tetrahydropyrane compounds, a process for their production and a pharmaceutical composition containing the same
JPH04149166A (en) 1990-10-12 1992-05-22 Nippon Kayaku Co Ltd Novel keto acid amide derivative
EP0494005A1 (en) 1990-12-28 1992-07-08 L'oreal Multicomponent agent or kit for the preparation of the sulphoconjugated forms of pyridino-, pyrimidino- or triazino-N-oxyde compounds and method of application thereof
WO1992016501A1 (en) 1991-03-20 1992-10-01 Vertex Pharmaceuticals Incorporated Tetrahydroxyalkane derivatives as inhibitors of hiv aspartyl protease
WO1992018478A1 (en) 1991-04-09 1992-10-29 Boehringer Mannheim Italia S.P.A. Heterocyclic amines useful in the therapy of asthma and inflammation of the respiratory tract
US5147877A (en) 1991-04-18 1992-09-15 Merck & Co. Inc. Semi-synthetic immunosuppressive macrolides
WO1992019745A1 (en) 1991-05-08 1992-11-12 Vertex Pharmaceuticals Incorporated Rfkbp: a novel prolyl isomerase and rapamycin/fk506 binding protein
WO1992019593A1 (en) 1991-05-09 1992-11-12 Vertex Pharmaceuticals Incorporated Novel immunosuppressive compounds
US5620971A (en) 1991-05-09 1997-04-15 Vertex Pharmaceuticals Incorporated Biologically active acylated amino acid derivatives
US5532248A (en) 1991-05-13 1996-07-02 Merck Co., Inc. O-aryl,O-alkyl, and O-alkenyl-macrolides having immunosuppressive activity
WO1992021313A2 (en) 1991-05-24 1992-12-10 Vertex Pharmaceuticals Incorporated Novel immunosuppressive compounds
EP0519819A1 (en) 1991-06-20 1992-12-23 L'oreal Composition for use to reduce hair loss and to induce and stimulate its growth, containing derivatives of 2,4,6-triaminopyrimidin-N-oxide and the new derivatives of 2,4,6-triaminopyrimidin-N-oxide
JPH05178824A (en) 1991-08-05 1993-07-20 Takeda Chem Ind Ltd Asparagine derivative and its use
US5189042A (en) 1991-08-22 1993-02-23 Merck & Co. Inc. Fluoromacrolides having immunosuppressive activity
US5457111A (en) 1991-09-05 1995-10-10 Abbott Laboratories Macrocyclic immunomodulators
US5208241A (en) 1991-09-09 1993-05-04 Merck & Co., Inc. N-heteroaryl, n-alkylheteroaryl, n-alkenylheteroaryl and n-alkynylheteroarylmacrolides having immunosuppressive activity
WO1993007269A1 (en) 1991-10-11 1993-04-15 Vertex Pharmaceuticals Incorporated ISOLATION OF AN Mr 52,000 FK506 BINDING PROTEIN AND MOLECULAR CLONING OF A CORRESPONDING HUMAN cDNA
WO1993013066A1 (en) 1991-12-20 1993-07-08 Syntex (U.S.A.) Inc. Cyclic amides of 3-amino-2-hydroxy-carboxylic acids as hiv-protease inhibitors
WO1993014072A1 (en) 1992-01-07 1993-07-22 British Bio-Technology Limited Amino acid derivatives as paf-receptor antagonists
WO1993014762A1 (en) 1992-01-27 1993-08-05 Merck & Co., Inc. 17β-HYDROXYBENZOYL-4-AZA-5α-ANDROST-1-EN-3-ONES USEFUL TO TREAT BALDNESS
WO1993018736A1 (en) 1992-03-19 1993-09-30 Armand Pardo Cosmetic hair care compositions for treating hair loss
EP0564924A2 (en) 1992-04-08 1993-10-13 Bayer Corporation 2-Oxoethyl derivatives as immunosuppressants
WO1993023548A2 (en) 1992-05-20 1993-11-25 Vertex Pharmaceuticals Incorporated METHOD OF DETECTING TISSUE-SPECIFIC FK506 BINDING PROTEIN MESSENGER RNAs AND USES THEREOF
EP0572365A2 (en) 1992-05-29 1993-12-01 NUOVO CONSORZIO SANITARIO NAZIONALE del Dott. Paolo Malizia & C. - S.A.S. Heteroprostanoids, process for their production and therapeutical use thereof
US5284840A (en) 1992-06-12 1994-02-08 Merck & Co., Inc. Alkylidene macrolides having immunosuppressive activity
US5284877A (en) 1992-06-12 1994-02-08 Merck & Co., Inc. Alkyl and alkenyl macrolides having immunosuppressive activity
WO1993025546A1 (en) 1992-06-17 1993-12-23 Merck Frosst Canada Inc. Bicyclic(azaaromatic)indoles as inhibitors of leukotriene biosynthesis
WO1994003476A1 (en) 1992-07-31 1994-02-17 Farmitalia Carlo Erba S.R.L. 17β-SUBSTITUTED 4-AZA-5α-ANDROSTAN-3-ONE DERIVATIVES
WO1994005639A1 (en) 1992-09-08 1994-03-17 Vertex Pharmaceuticals Incorporated Sulfonamide inhibitors of hiv-aspartyl protease
WO1994007858A1 (en) 1992-09-28 1994-04-14 Vertex Pharmaceuticals Incorporated 1-(2-oxo-acetyl)-piperidine-2-carboxylic acid derivatives as multi-drug-resistent cancer cell sensitizers
US5258389A (en) 1992-11-09 1993-11-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives
WO1994013629A1 (en) 1992-12-11 1994-06-23 Vertex Pharmaceuticals Incorporated Mannitol derivatives and their use as inhibitors of aspartyl protease
US5414083A (en) 1993-01-22 1995-05-09 Chemie Linz Gesellschaft M.B.H. Method for the production of N-cyclic and N,N'-dicyclic ureas and their use as chemical solvents
US5385918A (en) 1993-02-09 1995-01-31 Miles Inc. Aminomethylene-peptides as immunosuppressants
US5252579A (en) 1993-02-16 1993-10-12 American Home Products Corporation Macrocyclic immunomodulators
US5631017A (en) 1993-03-26 1997-05-20 Beth Israel Deaconess Medical Center, Inc. Topical application of buspirone for treatment of pathological conditions associated with immune responses
US5470878A (en) 1993-03-31 1995-11-28 Cell Therapeutics, Inc. Cell signaling inhibitors
US5424454A (en) 1993-05-18 1995-06-13 Celgene Corporation Process for the stereoselective preparation of l-alanyl-l-proline
US5319098A (en) 1993-05-18 1994-06-07 Celgene Corporation Process for the stereoselective preparation of L-alanyl-L-proline
WO1995002684A1 (en) 1993-07-16 1995-01-26 The Board Of Trustees Of The Leland Stanford Junior University Regulated apoptosis
EP0652229A2 (en) 1993-10-05 1995-05-10 ISAGRO S.p.A. Oligopeptides with fungicidal activity
WO1995012572A1 (en) 1993-11-04 1995-05-11 Abbott Laboratories Cyclobutane derivatives as inhibitors of squalene synthetase and protein farnesyltransferase
US5385908A (en) 1993-11-22 1995-01-31 American Home Products Corporation Hindered esters of rapamycin
US5543423A (en) 1994-11-16 1996-08-06 Vertex Pharmaceuticals, Incorporated Amino acid derivatives with improved multi-drug resistance activity
US5506228A (en) 1995-02-23 1996-04-09 Merck & Co., Inc. 2,6-diaryl pyridazinones with immunosuppressant activity
US5614547A (en) 1995-06-07 1997-03-25 Guilford Pharmaceuticals Inc. Small molecule inhibitors of rotamase enzyme
EP0823419A2 (en) 1996-08-09 1998-02-11 Takeda Chemical Industries, Ltd. Dimethylpropanediol compounds

Non-Patent Citations (122)

* Cited by examiner, † Cited by third party
Title
Ando, Takao et al., "Formation of Crossed Phenzine from the Reaction between Tetra-p-anisyl-and Tetra-p-totyl-hydrazines in Liquid Sulphur Dioxide," Chem. Comm., S. Chem. Comm., 1975, 989.
Andrus, Merrit B., "Stucture-based design of an acyclic ligand that bridges FKBP12 and calcineurin," J. Am. Chem. Soc., 1993, 115(2), 10420-1.
Armistead, D.M. et al., "Design, synthesis and structure of non-macrocyclic inhibitors of FKBP12, the major binding protin for the immunosuppressant FK506," Acta Crystallogr. 1995, D51(4), 522-8.
Askin, D. et al., "Effecient Degradation of FK-506 to a versatile synthetic intermediate," J. Org. Chem., 1990, 55(20), 5451-4.
Baader, Ekkehard et al., "Inhibition of prolyl 4-hydroxylase by oxalyl amino acid derivatives in vitro in isolated microsomes and in embryonic chicken tissues," Biochem. J., 1994, 300(2), 525-30.
Baumann, K. et al., "Synthesis and oxidative cleavage of the major equilibrium products of ascomycin and Fk 506," Tetrahedron Lett., 1995, 26(13), 2231-4.
Bender, D., et al., "Periodate oxidation of alpha-keto Y-lactams. Enol oxidation and beta-lactam formation. Mechanism of periodate hydroxylation reactions," J. Org. Chem., 1978, 43(17), 3354-62.
Bender, D., et al., "Periodate oxidation of α-keto Y-lactams. Enol oxidation and β-lactam formation. Mechanism of periodate hydroxylation reactions," J. Org. Chem., 1978, 43(17), 3354-62.
Birkenshaw, T.N. et al., "Synthetic FKBP12 Ligands. Design and Synthesis of Pyranose Replacements," Bioorganic & Medicinal Chemistry Letters, (1994) 4:21, 2501-2506.
Boulmedais, Ali et al., "Stereochemistry of Electrochemical Reduction of Optically Active alpha-ketoamides. II. Electroreduction of benzoylformamides derived form S-(-)-proline," Bull-Soc. Chim. Fr., 1989, (2), 185-91. (French).
Boulmedais, Ali et al., "Stereochemistry of Electrochemical Reduction of Optically Active α-ketoamides. II. Electroreduction of benzoylformamides derived form S-(−)-proline," Bull-Soc. Chim. Fr., 1989, (2), 185-91. (French).
Caffrey, M.V. et al., "Synthesis and Evaluation of Dual Domain Macrocyclic FKBP12 Ligands," Bioorganic & Medicinal Chemistry Letters, (1994) 4:21, 2507-2510.
Cameron, Andrew et al., "Immunophilin FK506 binding protein associated with inositol 1,4,5-triphosphate receptor modulates calcium flux," Proc. Natl. Acad. Sci. USA, 1995, 92, 1784-1788.
Caufield, Craig E. and Musser, John H., "Macrocyclic Immunomodulators," Annual Reports in Medicinal Chemistry, Johns (Ed.), Academic Press, Chapter 21, 195-204, 1989.
Chakaraborty, Tushar K., "Studies towards the development of cyclic peptide-based analogs of macrolide immunosuppressants," Pure Appl. Chem., 1996, 68(3), 565-568.
Chakraborty, TK et al., "Design and Synthesis of a rapamycin-based high affinity binding FKBP12 ligand," Chem. Biol., 1995, 2(3), 157-61.
Coleman, R., and Danishefsky, S., "Degradation and manipulations of the immunosuppressant FK506: preparation of potential synthetic intermediates," Heterocycles, 1989, 28(1), 157-61.
Colombo, L. et al., "Enantioselective synthesis of secondary alcohols in the presence of chiral ligands," Tetrahedron, 1982, 38(17), 2725-7.
Cunliffe, C. Jane et al., "Novel inhibitors of prolyl 4-hydroxylase. 3. Inhibition by the substrate analog N-oxaloglycine and its derivatives," J. Med. Chem., 1992, 35 (14), 2652-8.
Cushman, D.W. et al., "Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids," Biochemistry, 1977, 16(25), 5484-91.
Dawson, T.M. et al., "The immunophilins, FK506 binding and cyclophilin, are discretely localized in the brain: relationship to calcineurin," Neuroscience, 1994, 62(2), 569-80.
Dawson, Ted M. et al., "Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity," Proc. Natl. Acad. Sci. USA, 1993, 90, 9808-12.
Effenberger F. et al., "Diastereoselective addition of benzenesulfenyl chloride to 1-acryloylproline esters," Chemical Abstracts, 1989, 110:154846h.
Egbertson, M. and Danishefsky, S., "A synthetic route to the tricarbonyl region of FK-506," J. Org. Chem., 1989, 54(1), 11-12.
Feutren, Gilles, "The Optimal use of Cyclosporin A in Autoimmune Diseases," J. of Autoimmunity, 1992, 5, 183-95.
Finberg, Robert W. et al., "Prevention of HIV-1 Infection and Preservation of CD4 Function by the Binding of CPFs to gp120," Science, 1990, 249, 287-91.
Fisher, Matthew et al., "On the remarkable propensity for carbon-carbon bond cleavage reactions in teh C(8)-C(10) region of FK-506," J. Org. Chem., 1991, 56(8), 2900-7.
Fry, Lionel, "Psoriasis: Immunopathology and Long-term treatment with Cyclosporin," J. of Autoimmunity, 1992, 5, 277-83.
Furber, M. et al., "Studies relating to the immunosuppressive activitiy of FK506," Tetrahedron Lett., 1993, 34(8), 1351-4.
Furber, Mark, "FKBP-12-ligand-calceineurin interactions: analogs of SBL506," J. Am. Chem. Soc., 1995, 117(27), 7267-8.
Gold, Bruce R., et al., "The Immunosuppressant FK506 Increases the Rate of Axonal Regeneration in Rat Sciatic Nerve," J. Neuroscience, 1995, 15(11):7509-7516.
Goodfellow, Val S. et al., "p-Nitrophenyl 3-diazopyruvate and diazopyruvamides, a New Family of Photoactivatable Cross-Linking Bioprobes," Biochemistry, 28(15), 6346-60.
Goulet, Mark T. and Boger, Joshua, "Degradative studies on the tricarbonyl containing macrolide rapamycin," Tetrahedron Lett., 1991, 32(45), 6454.
Goulet, Mark T. et al., "Construction of the FK-506 analog from rapamycin-derived materials," Tetrahedron Lett., 1991, 32(36), 4627-30.
Goulet, Mark T., and Boger, Joshua, "Degradative studies on the tricarbonyl containing macrolide rapamycin," Tetrahedron Lett., 1990, 31(34), 4845-8.
Haeusler, Johannes and Schmidt, Ulrich, "Amino acids and peptides. IX. Pyruvoyl amino acids," Chem. Ber., 1974, 107(1), 145-51. (German).
Harding, M.W., et al., "A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase," Nature Lett., 1989, 341, 758-60.
Hauske, J.R. et al., "Design and Synthesis of Novel FKBP Inhibitors," J. of Medicinal Chemistry, (1992) 35, 4284-4296.
Hauske, James R. et al., "Investigation of the effects of synthetic, non-cytotoxic immunophilin inhibitors on MDR," Bioorg. Med. Chem.. Lett., 1994, 4(17), 2097-102.
Hayward, C.M. et al., "An application of the Suarez reaction to the regiospecific synthesis of the C28-C42 segment of rapamycin," 3989-92.
Hayward, C.M. et al., "Total Synthesis of rapamycin via a novel titanium-mediated aldol macrocyclization reaction," J. Am. Chem. Soc., 1993, 115(20), 9345-6.
Hearn, Walter R., and Worthington, Robert E., "L-Proline-N-oxalic anhydride," J. Org. Chem., 1967, 32(12), 4072-4.
Holt, D.A. et al., "Design, Synthesis, and Kinetic Evaluation of High-Affinity FKBP Ligands and the X-ray Crystal Structures of Their Complexes with FKBP12," J. Am. Chem. Soc., (1993) 115, 9925-9938.
Holt, D.A. et al., "Structure-Activity Studies of Nonmacrocyclic Rapamycin Derivatives," Bioorganic & Medicinal Chemistry Letter, (1993) 3:10, 1977-1980.
Holt, D.A. et al., "Structure-Activity Studies of Synthetic FKBP Ligands as Peptidyl-prolyl Isomers Inhibitors," Bioorganic & Medicinal Chemistry Letters, (1994) 4:2, 315-320.
Hovarth, R., et al., "An application of the Evans-Prasad 1,3-Syn diol synthesis to a stereospecific synthesis of the C10-C27 segment of rapamycin," Tetrahedron Lett., 1993, 34(25), 3993-3996.
Iwabuchi, T. et al., "Effects of immunosuppressive peptidyl-prolyl cis-trans isomerase (PPIase inhibitors, cyclosporin A, FK506, ascomycin and rapamycin, on hair growth initiation in mouse: immunosuppression is not required for hair growth," J. of Deramatol. Sci., (1995) 9:1, 64-69.
Jiang, H. et al., "Induction of anagen in telogen mouse skin by topical application of FK506, a potent immunosuppressant," J. Invest. Dermatol., (1995) 104:4, 523-525. Abstract.
Jones, A. et al., "A formal synthesis of FK-506. Exploration of some alternatives to macrolactamization," J. Org. Chem., 1990, 55(9), 2786-97.
Jones, T. et al., "Chemistry of tricarbonyl hemiketals and application of Evans technology to the total synthesis of the immunosuppressant (-)-FK-506," J. Am. Chem. Soc., 1990, 112(8), 2998-3017.
Jones, T. et al., "Chemistry of tricarbonyl hemiketals and application of Evans technology to the total synthesis of the immunosuppressant (−)-FK-506," J. Am. Chem. Soc., 1990, 112(8), 2998-3017.
Kaczmar, et al., Makromol. Chem., 1976, 177, 1981-9 (German).
Karle, Isabella L. et al., "Coformation of the oxalamide group in retro-bispeptides. Three crystal structures," Int. J. Pept. Protein Res., 1994, 43(2), 160-5.
Kino, Toru et al., "FK-506, A novel immunosuppressnt isolateded from A streptomyces," J. of Antibiotics, 1987, 40(9), 1249-55.
Kocienski, P. et al., "A synthesis of the C(1)-C(15) segment of tsukubaenolide (FK506)," Tetrahedron Lett., 1988, 29(35), 4481-4.
Krit, N.A. et al., "Impact of the nature of alkyl radical on the biological activity of N-carboxyalkyl dipeptides," Khim.-Farm. Zh., 1991, 25(7), 44-6. (Russian).
Linde, Robert G. et al., "Straightforward synthesis of 1,2,3-tricarbonyl systems," J. Org. Chem., 1991, 56(7), 2534-8.
Luengo, J. et al., "Structure-activity studies of rapamycin analogs: evidence that the C-7 methodoxy group is part of the effector domain and positioned at the FKBP:12-FRAP interface," Chem. Biol., 1995, 2(7), 471-81.
Luengo, J. et al., "Studies on the chemistry of rapamycin: novel transformation under Lewis-acid catalysis," Tetrahedron Lett., 1993, 34(6), 991-4.
Luengo, J.I. et al., "Synthesis and Structure-Activity Relationships of Macrocyclic FKBP Ligands," Bioorganic & Medicinal Chemistry Letters, (1994) 4:2, 321-324.
Luengo, Juan I. et al., "Efficient removal of pipecolinate from rapamycin and FK506 by reaction with tetrabutylammonium cyanide," Tetrahedron Lett., 1993, 34(29), 4599-602.
Lyons, W. Ernest et al., "Neronal Regeneration Enhances the Expression of the Immunophilin FKBP-12," The Journal of Neuroscience, 1995, 15, 2985-94.
Marshall, J.A. et al., Convenient synthesis of dioxopiperazines via aminolysis of .alpha.-(pyruvylamino) esters, Synth. Commun., 1975, 5(3), 237-44.
Mashkovskii, M.D. et al., "1-[4-(2-Hydroxy-3-tert-butylaminopropoxy)-indole-3-yl (5-acetamido-1-(S)-carboxypentyl)-DL-alanyl]-L-proline dihydrochloride, a new angiotensin-converting enzyme inhibitor with beta-adrenoblocking properties," Khim.-Farm. Zh., 1993, 27(10), 16-20. (Russian).
Mashkovskii, M.D. et al., "1-[4-(2-Hydroxy-3-tert-butylaminopropoxy)-indole-3-yl (5-acetamido-1-(S)-carboxypentyl)-DL-alanyl]-L-proline dihydrochloride, a new angiotensin-converting enzyme inhibitor with β-adrenoblocking properties," Khim.-Farm. Zh., 1993, 27(10), 16-20. (Russian).
Maurer, Marcus, et al., Hair Growth Modulation by Topical Immunophilin Ligands, Am. J. Path. 150:1433-41 (1997).
Munoz, Benito et al., "alpha-Ketoamide Phe-Pro isostere as a new core structure for the inhibition of HIV protease," Bioorg. Med. Chem., 1994, 2(10), 1085-90.
Munoz, Benito et al., "α-Ketoamide Phe-Pro isostere as a new core structure for the inhibition of HIV protease," Bioorg. Med. Chem., 1994, 2(10), 1085-90.
Nakatsuka, M et al. "Total Synthesis of FK506 and an FKBP Reagent, (C8, C9-13C2)-FK-506," J. Am. Chem Soc., 1990, 112 (14), 5583-90..
Nelson, F. et al., "A novel ring contraction of rapamycin," Tetrahedron Lett., 1994, 35(41), 7557-60.
Pattenden, Gerald and Tankard, Mark, "Facile Synthesis of the tricarbonyl subunit in the immunosuppressant rapamycin," Tetrahedron Lett., 1993, 34(16), 2677-80.
Ranganathan, Darshan et al., "Oxalopeptides as core motifs for protein design," J. Chem. Soc., 1993, (1), 92-4.
Ranganathan, Darshan et al., "Protein Backbone Modification by Novel Calpha-C Side-Chain Scission," 1994, J. Am. Chem. Soc., 116(15), 6545-57.
Ranganathan, Darshan et al., "Protein Backbone Modification by Novel Cα-C Side-Chain Scission," 1994, J. Am. Chem. Soc., 116(15), 6545-57.
Rao, A.V. Rama and Desibhatla, Vidyanand, "Studies directed towards the syntesis of rapamycin: stereoselective synthesis of C-1 to C-15 segment," Tetrahedron Lett., 1993, 34(44), 7111-14.
Rao, A.V. Rama et al., "Studies directed towards the synthesis of immunosuppressive agent FK-506: synthesis of the entire bottom half," Tetrahedron Lett., 1991, 32(9), 1251-4.
Rao, A.V., et al., "Studies directed towards the synthesis of immunosuppressive agent FK-506: construction of the tricarbonyl moiety," Tetrahedron Lett., 1990, 31(10), 1439-42.
Skotnicki, Jerauld et al., "Ring expanded rapamycin derivatives," Tetrahedron Lett., 1994, 35(2), 201-2.
Skotnicki, Jerauld et al., "Synthesis of secorapamycin esters and amides," Tetrah. Lett., 1994, 35(2), 197-200.
Slee, Deborah H. et al., Selectivity in the Inhibition of HIV and FIV Protease: Inhibitory and Mechanistic Studies of Pyrrolidine-Containing alpha-Keto Amide and Hydroxyethylamine Core Structures, J. Am. Chem. Soc., 1995, 117(48), 1187-78.
Slee, Deborah H. et al., Selectivity in the Inhibition of HIV and FIV Protease: Inhibitory and Mechanistic Studies of Pyrrolidine-Containing α-Keto Amide and Hydroxyethylamine Core Structures, J. Am. Chem. Soc., 1995, 117(48), 1187-78.
Soai, Kenso and Hasegawa, Hitoshi, "Diastereoselective reduction of chiral alpha-ketoamides derived from (S)-proline esters with sodium borohydride. Preparation of optically active alpha-hydroxy acids," J. Chem. Soc., 1985, 1(4), 769-72.
Soai, Kenso and Hasegawa, Hitoshi, "Diastereoselective reduction of chiral α-ketoamides derived from (S)-proline esters with sodium borohydride. Preparation of optically active α-hydroxy acids," J. Chem. Soc., 1985, 1(4), 769-72.
Soai, Kenso and Ishizaki, Miyuki, "Asymmetric Synthesis of Functionalized tertiary alcohols by diastereoselective allylation of chiral alpha-keto amides derived from (S)-proline esters: control of stereochemistry based on saturated coordination of Lewis acid," J. Org. Chem., 1986, 51(17) 3290-5. (English).
Soai, Kenso and Ishizaki, Miyuki, "Asymmetric Synthesis of Functionalized tertiary alcohols by diastereoselective allylation of chiral α-keto amides derived from (S)-proline esters: control of stereochemistry based on saturated coordination of Lewis acid," J. Org. Chem., 1986, 51(17) 3290-5. (English).
Soai, Kenso and Ishizaki, Miyuki, "Diastereoselective asymmetric allylation of chiral alpha-keto amides with allyltrimethylsilane. Preparation of protected homoallylic alcohols," J. Chem. Soc., 1984, 15, 1016-1017.
Soai, Kenso and Ishizaki, Miyuki, "Diastereoselective asymmetric allylation of chiral α-keto amides with allyltrimethylsilane. Preparation of protected homoallylic alcohols," J. Chem. Soc., 1984, 15, 1016-1017.
Soai, Kenso et al., "Asymmetric Allylation of alpha-keto amides Derived from (S)-proline esters," Pept. Chem., 1986, 24, 327-330.
Soai, Kenso et al., "Asymmetric Allylation of α-keto amides Derived from (S)-proline esters," Pept. Chem., 1986, 24, 327-330.
Soai, Kenso et al., "Asymmetric synthesis of both eaniomers of alpha-hydroxy acids by the diastereoselective reduction of chiral alpha-keto amides with complex metal hydrides in the presence of a metal salt," Chem. Lett., 1986, 11, 1897-900.
Soai, Kenso et al., "Asymmetric synthesis of both eaniomers of α-hydroxy acids by the diastereoselective reduction of chiral α-keto amides with complex metal hydrides in the presence of a metal salt," Chem. Lett., 1986, 11, 1897-900.
Steffan, Robert J. et al., "Base catalyzed degradations of rapamycin," Tetrahedron Lett., 1993, 34(23), 3699-702.
Steglich, Wolfgang and Hinze, Sabine, "A rational synthesis of N-trifluroacetylamino acids," Synthesis, 1976, 8, 399-401. (German).
Steglich, Wolfgang et al., "Activated carboxylic acid derivatives. II. A simple synthesis of 2-oxycarboxylic acid amides, N-(2-oxoacyl)amino acid esters and 2-oxocarboxylic acid hydrazides," Synthesis, 1978, 8, 622-4. (German).
Steiner, et al., Chemical Abstract, vol. 126:272710, 1997.
Steiner, J.P. et al., "Nonimmunosuppressive Ligands for Neuroimmunophilins Promote Nerve Extension In Vitro and In Vivo," Society for Neuroscience Abstracts, 1996, 22, 297.13.
Steiner, Joseph P. et al., "High brain densities of the immunophilin FKBP colocalized with calcineurin," Nature, 1992, 358, 584-7.
Steiner, Joseph P., et al., "Neurotrophic Actions of Nonimmunosuppressive Analogues of Immunosuppressive Drugs FK506, Rapamycin and Cyclosporin A," Nat. Med. 3(4):421-428.
Steiner, Joseph P., et al., "Neurotrophic Immunophilin Liagnds Stimulate Structural and Functional Recovery in Neurodegenerative Animal Models," 1997, Proc. Natl. Aced. Sci. USA, 94:2019-2024.
Stocks, M. et al., "Macrocyclic ring closures employing the intramolecular Heck reaction," Tetrahedron Lett., 1995, 36(36), 6555-8.
Stocks, M. et al., "The contribution to the binding of the pyranoside sustituents in the excised binding domain of FK-506," Bioorg. Med. Chem. Lett., 1994, 4(12), 1457-60.
Synder, S.H. et al., "Immunophilins and the Nervous System," Nature Medicine, (1995) 1:1, 32-37.
Tanaka, H. et al., "Structure of FK506, a novel imunosuppressant isolated from Streptomyces," J. Am. Chem. Soc., 1987, 109(16), 5031-3.
Tatlock, J. et al., "High affinity FKBP-12 ligands from (R)-(-)-carvone. Synthesis and evaluation of FK506 pyranose ring replacements," Bioorg. Med. Chem. Lett., 1995, 5(21), 2489-94.
Tatlock, J. et al., "High affinity FKBP-12 ligands from (R)-(−)-carvone. Synthesis and evaluation of FK506 pyranose ring replacements," Bioorg. Med. Chem. Lett., 1995, 5(21), 2489-94.
Teague, S. et al., "Synthesis of FK506-cyclosporin hybrid macrocycles," Bioorg. Med. Chem. Lett., 1995, 5(20), 2341-6.
Teague, S.J. et al., "Synthesis and Study of a Non-Macrocyclic FK506 Derivative," Bioorganic & Medicinal Chemistry Letters, (1994) 4:13, 1581-1584.
Teague, S.J. et al., "The Affinity of the Excised Binding Domain of FK-506 for the Immunophilin FKBP12," Bioorganic & Medicinal Chemistry Letters, (1993) 3:10, 1947-1950.
Tugwell, Peter, "Clyclosporin in the Treatment of Rheumatoid Arthritis," J. of Autoimmunity, 1992, 5, 231-40.
Waldmann, Herbert, "Proline benzyl ester as chiral auxilary in Barbier-type reactions in aqueous solution," 1990, Synlett, 10, 627-8.
Wang, C.P. et al., "A high performance liquid chromatographic method for the determination of rapamycin {sirolimus} in rat serum, plasma, and blood and in monkey serum," J. Liq. Chromatogr., 1995, 18(9), 1801-8.
Wang, C.P. et al., "High performance liquid chromatographic isolation and spectroscopic characterization of three major metabolites from the plasma of rats receiving rapamycin (sirolimus) orally," J. Liq. Chromatogr., 1995, 18(13), 2559-68.
Wang, G.T. et al., "Synthesis and FKBP Binding of Small Molecule Mimics of the Tricarbonyl Region of FK506," Bioorganic and Medicinal Chemistry Letters, (1994) 4:9, 1161-1166.
Wasserman, H.H. et al., "Synthesis of the tricarbonyl region of FK-506 through an amidosphere," J. Org. Chem., 1989, 54(12), 2785-6.
Whitesell, J.K. et al., "Asymmetric Induction. Reduction, Nucleophilic Addition to, Ene Reactions of Chiral alpha-Ketoesters," J. Chem. Soc., Chem Commun., 1983, 802.
Whitesell, J.K. et al., "Asymmetric Induction. Reduction, Nucleophilic Addition to, Ene Reactions of Chiral α-Ketoesters," J. Chem. Soc., Chem Commun., 1983, 802.
Williams, D.R. and Benbow, J.W., "Synthesis of the alpha,beta diketo amide segment of the novel immunosuppressive FK506," J. Org. Chem., 1988, 53(191), 4643-4.
Williams, D.R. and Benbow, J.W., "Synthesis of the α,β diketo amide segment of the novel immunosuppressive FK506," J. Org. Chem., 1988, 53(191), 4643-4.
Yamamoto, S. et al., "Stimulation of hair growth by topical application of FK506, a potent immunosuppressive agent," J. Invest. Dermatol, (1994) 102:2, 160-164. Abstract.
Yamashita, D.S. et al., "Design, Synthesis and Evaluation of Dual Domain FKBP Ligands," Bioorganic & Medicinal Chemistry, (1994) 4:2, 325-328.
Yohannes, Daniel et al., "Degradation of rapamycin: retrieval of major intact subunits," Tetrahedron Lett., 1992, 33(49), 7469-72.
Yohannes, Daniel et al., "Degradation of rapamycin: synthesis of a rapamycin-derived fragment containing the tricarbonyl and triene sectors,"Tetrahedron Lett., 1993, 34(13), 2075-8.

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010029263A1 (en) * 1997-06-04 2001-10-11 Gpi Nil Holdings, Inc. Novel pyrrolidine carboxylate hair revitalizing agents
US20020198250A1 (en) * 1997-06-04 2002-12-26 Steiner Joseph P. Pyrrolidine derivative hair growth compositions and uses
US20050059693A1 (en) * 1997-06-04 2005-03-17 Gpi Nil Holdings, Inc. Heterocyclic thioester and ketone hair growth compositions and uses
US6943187B2 (en) 1997-06-04 2005-09-13 Gpi Nil Holdings, Inc. Pyrrolidine derivative hair growth compositions and uses
US20010041733A1 (en) * 1998-06-03 2001-11-15 Gpi Nil Holdings, Inc. Heterocyclic ester and amide hair growth compositions and uses
US6429215B1 (en) 1998-06-03 2002-08-06 Gpi Nil Holdings, Inc. N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses

Also Published As

Publication number Publication date
CA2292910C (en) 2008-09-02
US6004993A (en) 1999-12-21
TW518220B (en) 2003-01-21
ZA984778B (en) 1999-02-24
US20020037924A1 (en) 2002-03-28
US6187806B1 (en) 2001-02-13
AU7716998A (en) 1998-12-21
AU7716498A (en) 1998-12-21
TW490307B (en) 2002-06-11
JP4068164B2 (en) 2008-03-26
US6239164B1 (en) 2001-05-29
EP0998263A1 (en) 2000-05-10
US20010036952A1 (en) 2001-11-01
WO1998055091A1 (en) 1998-12-10
ATE275930T1 (en) 2004-10-15
AU751057B2 (en) 2002-08-08
US20010029263A1 (en) 2001-10-11
CA2292965A1 (en) 1998-12-10
EP1479373B1 (en) 2007-01-10
US5945441A (en) 1999-08-31
DE69836878D1 (en) 2007-02-22
MXPA99010886A (en) 2003-08-01
US6177455B1 (en) 2001-01-23
JP2002510301A (en) 2002-04-02
ZA984621B (en) 1999-02-24
TW501931B (en) 2002-09-11
EP0983054A1 (en) 2000-03-08
EP1479373A1 (en) 2004-11-24
ZA984783B (en) 1999-02-24
CA2292965C (en) 2007-11-13
DE69826267D1 (en) 2004-10-21
WO1998055090A1 (en) 1998-12-10
CA2292910A1 (en) 1998-12-10
ES2229498T3 (en) 2005-04-16
JP2002510302A (en) 2002-04-02
US6194440B1 (en) 2001-02-27
EP0983054B1 (en) 2004-09-15
DE69826267T2 (en) 2005-11-17

Similar Documents

Publication Publication Date Title
US6191125B1 (en) Small molecule pipecolic acid derivative hair growth compositions and uses
US6274617B1 (en) Heterocyclic ester and amide hair growth compositions and uses
US6187784B1 (en) Pipecolic acid derivative hair growth compositions and uses
AU764032B2 (en) Small molecule carbamate or urea hair growth compositions and uses
US6172087B1 (en) N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
EP1083874B1 (en) Use of a compound for the preparation of a medicament for treating alopecia or promoting hair growth in an animal
AU760663B2 (en) Small molecule sulfonamide hair growth compositions and uses
AU761737B2 (en) N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
US6187796B1 (en) Sulfone hair growth compositions and uses
AU761083B2 (en) Pipecolic acid derivative hair growth compositions and uses
US6271244B1 (en) N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses
US6274602B1 (en) Heterocyclic thioester and ketone hair growth compositions and uses
US20020010205A1 (en) N-linked sulfone of heterocyclic thioester hair growth compositions and uses
EP1083873B1 (en) Heterocyclic thioester and ketone hair growth compositions and uses
MXPA00011850A (en) Small molecule pipecolic acid derivative hair growth compositions and uses

Legal Events

Date Code Title Description
AS Assignment

Owner name: GUILFORD PHARMACEUTICALS INC., MARYLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:STEINER, JOSEPH P.;HAMILTON, GREGORY S.;REEL/FRAME:009349/0338

Effective date: 19980706

AS Assignment

Owner name: GPI NIL HOLDINGS, INC., DELAWARE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:GUILFORD PHARMACEUTICALS INC.;REEL/FRAME:009355/0460

Effective date: 19980707

FPAY Fee payment

Year of fee payment: 4

AS Assignment

Owner name: GLIAMED, INC., NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:GPI IP, LLC, D/B/A MGL PHARMA;REEL/FRAME:019477/0568

Effective date: 20070405

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20090220

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载